View source for Interleukin 6

{{Short description|Cytokine protein}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox gene}}
'''Interleukin 6''' ('''IL-6''') is an [[interleukin]] that acts as both a pro-inflammatory [[cytokine]] and an anti-inflammatory [[myokine]]. In humans, it is encoded by the ''IL6'' [[gene]].<ref name="pmid3294161">{{cite journal | vauthors = Ferguson-Smith AC, Chen YF, Newman MS, May LT, Sehgal PB, Ruddle FH | title = Regional localization of the interferon-beta 2/B-cell stimulatory factor 2/hepatocyte stimulating factor gene to human chromosome 7p15-p21 | journal = Genomics | volume = 2 | issue = 3 | pages = 203–208 | date = April 1988 | pmid = 3294161 | doi = 10.1016/0888-7543(88)90003-1 }}</ref>

In addition, [[osteoblast]]s secrete IL-6 to stimulate [[osteoclast]] formation.  [[Smooth muscle cell]]s in the [[tunica media]] of many blood vessels also produce IL-6 as a pro-inflammatory [[cytokine]].  IL-6's role as an anti-inflammatory myokine is mediated through its inhibitory effects on [[TNF]] and [[IL1A|IL-1]] and its activation of [[Interleukin 1 receptor antagonist|IL-1ra]] and [[Interleukin 10|IL-10]].

There is some early evidence that IL-6 can be used as an [[inflammatory markers|inflammatory marker]] for severe [[COVID-19]] infection with poor prognosis, in the context of the wider [[COVID-19 pandemic|coronavirus pandemic]].<ref>{{cite web |title=Raised troponin and interleukin-6 levels are associated with a poor prognosis in COVID-19 |url=https://cardiacrhythmnews.com/raised-troponin-and-interleukin-6-levels-are-associated-with-a-poor-prognosis-in-covid-19/ |date=2 April 2020 |work=Cardiac Rhythm News}}</ref>

== Function ==

=== Immune system ===

IL-6 is secreted by [[macrophages]] in response to specific microbial molecules, referred to as [[pathogen]]-associated molecular patterns ([[Pathogen-associated molecular pattern|PAMP]]s). These PAMPs bind to an important group of detection molecules of the [[innate immune system]], called [[pattern recognition receptor]]s (PRRs), including Toll-like receptors ([[Toll-like receptor|TLR]]s). These are present on the cell surface and intracellular compartments and induce [[intracellular signaling cascade]]s that give rise to inflammatory cytokine production.  IL-6 is an important mediator of [[fever]] and of the [[acute phase response]].

IL-6 is responsible for stimulating acute phase protein synthesis, as well as the production of [[neutrophils]] in the [[bone marrow]]. It supports the growth of [[B cells]] and is antagonistic to [[regulatory T cell]]s.

=== Metabolic ===

It is capable of crossing the [[blood–brain barrier]]<ref name="pmid7845624">{{cite journal | vauthors = Banks WA, Kastin AJ, Gutierrez EG | title = Penetration of interleukin-6 across the murine blood–brain barrier | journal = Neuroscience Letters | volume = 179 | issue = 1–2 | pages = 53–56 | date = September 1994 | pmid = 7845624 | doi = 10.1016/0304-3940(94)90933-4 | s2cid = 22712577 }}</ref> and initiating synthesis of [[Prostaglandin E2|PGE<sub>2</sub>]] in the [[hypothalamus]], thereby changing the body's temperature setpoint.  In muscle and fatty tissue, IL-6 stimulates energy mobilization that leads to increased [[body temperature]]. At 4{{nbsp}}°C, both the oxygen consumption and core temperature were lower in IL-6<sup>-/-</sup> compared with wild-type mice, suggesting a lower cold-induced thermogenesis in IL-6<sup>-/-</sup> mice.<ref name="pmid16456579">{{cite journal | vauthors = Wernstedt I, Edgley A, Berndtsson A, Fäldt J, Bergström G, Wallenius V, Jansson JO | title = Reduced stress- and cold-induced increase in energy expenditure in interleukin-6-deficient mice | journal = American Journal of Physiology. Regulatory, Integrative and Comparative Physiology | volume = 291 | issue = 3 | pages = R551–R557 | date = September 2006 | pmid = 16455769 | doi = 10.1152/ajpregu.00514.2005 }}</ref>

In the absence of inflammation 10–35% of circulating IL-6 may come from adipose tissue.<ref name="pmid14988384" /> IL-6 is produced by [[adipocytes]] and is thought to be a reason why obese individuals have higher endogenous levels of [[C-reactive protein|CRP]].<ref name="Bastard27041999">{{cite journal | vauthors = Bastard JP, Jardel C, Delattre J, Hainque B, Bruckert E, Oberlin F | title = Evidence for a link between adipose tissue interleukin-6 content and serum C-reactive protein concentrations in obese subjects | journal = Circulation | volume = 99 | issue = 16 | pages = 2221–2222 | date = April 1999 | pmid = 10217702 | doi = 10.1161/circ.99.16.2219/c | doi-access = free }}</ref> IL-6 may exert a tonic suppression of body fat in mature mice, given that IL-6 [[gene knockout]] causes mature onset obesity.<ref name="Wallenius_2002">{{cite journal | vauthors = Wallenius V, Wallenius K, Ahrén B, Rudling M, Carlsten H, Dickson SL, Ohlsson C, Jansson JO | title = Interleukin-6-deficient mice develop mature-onset obesity | journal = Nature Medicine | volume = 8 | issue = 1 | pages = 75–79 | date = January 2002 | pmid = 11786910 | doi = 10.1038/nm0102-75 | s2cid = 7111589 }}</ref><ref name="Matthews_2010">{{cite journal | vauthors = Matthews VB, Allen TL, Risis S, Chan MH, Henstridge DC, Watson N, Zaffino LA, Babb JR, Boon J, Meikle PJ, Jowett JB, Watt MJ, Jansson JO, Bruce CR, Febbraio MA | title = Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance | journal = Diabetologia | volume = 53 | issue = 11 | pages = 2431–2441 | date = November 2010 | pmid = 20697689 | doi = 10.1007/s00125-010-1865-y | s2cid = 12970519 }}</ref><ref name="Di_Gregorio_2004">{{cite journal | vauthors = Di Gregorio GB, Hensley L, Lu T, Ranganathan G, Kern PA | title = Lipid and carbohydrate metabolism in mice with a targeted mutation in the IL-6 gene: absence of development of age-related obesity | journal = American Journal of Physiology. Endocrinology and Metabolism | volume = 287 | issue = 1 | pages = E182–E187 | date = July 2004 | pmid = 15191885 | doi = 10.1152/ajpendo.00189.2003 }}</ref> Moreover, IL-6 can suppress body fat mass via effects at the level of the CNS.<ref name="Wallenius_2002" />  The antiobesity effect of IL-6 in rodents is exerted at the level of the brain, presumably the hypothalamus and the [[hindbrain]].<ref name="pmid12054638">{{cite journal | vauthors = Wallenius K, Wallenius V, Sunter D, Dickson SL, Jansson JO | title = Intracerebroventricular interleukin-6 treatment decreases body fat in rats | journal = Biochemical and Biophysical Research Communications | volume = 293 | issue = 1 | pages = 560–565 | date = April 2002 | pmid = 12054638 | doi = 10.1016/S0006-291X(02)00230-9 }}</ref><ref name="pmid19902173">{{cite journal | vauthors = Sadagurski M, Norquay L, Farhang J, D'Aquino K, Copps K, White MF | title = Human IL6 enhances leptin action in mice | journal = Diabetologia | volume = 53 | issue = 3 | pages = 525–535 | date = March 2010 | pmid = 19902173 | pmc = 2815798 | doi = 10.1007/s00125-009-1580-8 }}</ref><ref name="pmid24523541">{{cite journal | vauthors = Campbell IL, Erta M, Lim SL, Frausto R, May U, Rose-John S, Scheller J, Hidalgo J | title = Trans-signaling is a dominant mechanism for the pathogenic actions of interleukin-6 in the brain | journal = The Journal of Neuroscience | volume = 34 | issue = 7 | pages = 2503–2513 | date = February 2014 | pmid = 24523541 | pmc = 6802757 | doi = 10.1523/JNEUROSCI.2830-13.2014 }}</ref> On the other hand, enhanced central IL-6 trans-signaling may improve energy and [[glucose homeostasis]] in obesity<ref name="pmid23136552">{{cite journal | vauthors = Rose-John S | title = IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6 | journal = International Journal of Biological Sciences | volume = 8 | issue = 9 | pages = 1237–1247 | date = 2012 | pmid = 23136552 | pmc = 3491447 | doi = 10.7150/ijbs.4989 }}</ref> Trans-signaling implicates that a soluble form of IL-6R (sIL-6R) comprising the extracellular portion of the receptor can bind IL-6 with a similar affinity as the membrane bound IL-6R. The complex of IL-6 and sIL-6R can bind to gp130 on cells, which do not express the IL-6R, and which are unresponsive to IL-6.<ref name="pmid23136552" />

Studies in experimental animals indicate that IL-6 in the CNS partly mediates the suppression of food intake and body weight exerted by [[Glucagon-like peptide-1 receptor|glucagon-like peptide-1 (GLP-1) receptor]] stimulation.<ref name="pmid24048027">{{cite journal | vauthors = Shirazi R, Palsdottir V, Collander J, Anesten F, Vogel H, Langlet F, Jaschke A, Schürmann A, Prévot V, Shao R, Jansson JO, Skibicka KP | title = Glucagon-like peptide 1 receptor induced suppression of food intake, and body weight is mediated by central IL-1 and IL-6 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 40 | pages = 16199–16204 | date = October 2013 | pmid = 24048027 | pmc = 3791711 | doi = 10.1073/pnas.1306799110 | doi-access = free | bibcode = 2013PNAS..11016199S }}</ref>

Outside the CNS, it seems that IL-6 stimulates the production of GLP-1 in the endocrine pancreas and the gut.<ref name="pmid22037645">{{cite journal | vauthors = Ellingsgaard H, Hauselmann I, Schuler B, Habib AM, Baggio LL, Meier DT, Eppler E, Bouzakri K, Wueest S, Muller YD, Hansen AM, Reinecke M, Konrad D, Gassmann M, Reimann F, Halban PA, Gromada J, Drucker DJ, Gribble FM, Ehses JA, Donath MY | title = Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells | journal = Nature Medicine | volume = 17 | issue = 11 | pages = 1481–1489 | date = October 2011 | pmid = 22037645 | pmc = 4286294 | doi = 10.1038/nm.2513 }}</ref> [[Amylin]] is another substance that can reduce body weight, and that may interact with IL-6.  Amylin-induced IL-6 production in the [[ventromedial hypothalamus]] (VMH) is a possible mechanism by which amylin treatment could interact with VMH [[leptin]] signaling to increase its effect on weight loss.<ref name="pmid25409701">{{cite journal | vauthors = Le Foll C, Johnson MD, Dunn-Meynell AA, Boyle CN, Lutz TA, Levin BE | title = Amylin-induced central IL-6 production enhances ventromedial hypothalamic leptin signaling | journal = Diabetes | volume = 64 | issue = 5 | pages = 1621–1631 | date = May 2015 | pmid = 25409701 | pmc = 4407855 | doi = 10.2337/db14-0645 }}</ref>

It is assumed that interleukin 6 in the liver activates the homologue of the human longevity gene [[Indy (gene)|mINDY]] expression via binding to its IL-6-receptor, which is associated with activation of the transcription factor [[STAT3]] (which binds to the binding site in the mIndy promoter) and thereby rise of [[citrate]] uptake and hepatic lipogenesis.<ref name="pmid28133767">{{cite journal | vauthors = von Loeffelholz C, Lieske S, Neuschäfer-Rube F, Willmes DM, Raschzok N, Sauer IM, König J, Fromm MF, Horn P, Chatzigeorgiou A, Pathe-Neuschäfer-Rube A, Jordan J, Pfeiffer AF, Mingrone G, Bornstein SR, Stroehle P, Harms C, Wunderlich FT, Helfand SL, Bernier M, de Cabo R, Shulman GI, Chavakis T, Püschel GP, Birkenfeld AL | title = The human longevity gene homolog INDY and interleukin-6 interact in hepatic lipid metabolism | journal = Hepatology | volume = 66 | issue = 2 | pages = 616–630 | date = August 2017 | pmid = 28133767 | pmc = 5519435 | doi = 10.1002/hep.29089 }}</ref><ref name="pmid28596784">{{cite journal | vauthors = Rogina B | title = INDY-A New Link to Metabolic Regulation in Animals and Humans | journal = Frontiers in Genetics | volume = 8 | issue =  | pages = 66 | date = 2017 | pmid = 28596784 | pmc = 5442177 | doi = 10.3389/fgene.2017.00066 | doi-access = free }}{{Creative Commons text attribution notice|cc=by4|from this source=yes}}</ref>

=== Central nervous system ===

Intranasally administered IL-6 has been shown to improve sleep-associated [[memory consolidation|consolidation]] of emotional memories.<ref name="pmid19546306">{{cite journal | vauthors = Benedict C, Scheller J, Rose-John S, Born J, Marshall L | title = Enhancing influence of intranasal interleukin-6 on slow-wave activity and memory consolidation during sleep | journal = FASEB Journal | volume = 23 | issue = 10 | pages = 3629–3636 | date = October 2009 | pmid = 19546306 | doi = 10.1096/fj.08-122853 | doi-access = free | s2cid = 38515607 }}</ref>

There are indications of interactions between GLP-1 and IL-6 in several parts of the brain. One example is the [[parabrachial nuclei]] of the [[pons]], where GLP-1 increases IL-6 levels<ref name="pmid25116706">{{cite journal | vauthors = Richard JE, Farkas I, Anesten F, Anderberg RH, Dickson SL, Gribble FM, Reimann F, Jansson JO, Liposits Z, Skibicka KP | title = GLP-1 receptor stimulation of the lateral parabrachial nucleus reduces food intake: neuroanatomical, electrophysiological, and behavioral evidence | journal = Endocrinology | volume = 155 | issue = 11 | pages = 4356–4367 | date = November 2014 | pmid = 25116706 | pmc = 4256827 | doi = 10.1210/en.2014-1248 }}</ref><ref name="pmid30889580">{{cite journal | vauthors = Anesten F, Mishra D, Dalmau Gasull A, Engström-Ruud L, Bellman J, Palsdottir V, Zhang F, Trapp S, Skibicka KP, Poutanen M, Jansson JO | title = Glucagon-Like Peptide-1-, but not Growth and Differentiation Factor 15-, Receptor Activation Increases the Number of Interleukin-6-Expressing Cells in the External Lateral Parabrachial Nucleus | journal = Neuroendocrinology | volume = 109 | issue = 4 | pages = 310–321 | date = 2019 | pmid = 30889580 | doi = 10.1159/000499693 | s2cid = 208014066 }}</ref> and where IL-6 exerts a marked anti-obesity effect.<ref name="pmid30865890">{{cite journal | vauthors = Mishra D, Richard JE, Maric I, Porteiro B, Häring M, Kooijman S, Musovic S, Eerola K, López-Ferreras L, Peris E, Grycel K, Shevchouk OT, Micallef P, Olofsson CS, Wernstedt Asterholm I, Grill HJ, Nogueiras R, Skibicka KP | title = Parabrachial Interleukin-6 Reduces Body Weight and Food Intake and Increases Thermogenesis to Regulate Energy Metabolism | journal = Cell Reports | volume = 26 | issue = 11 | pages = 3011–3026.e5 | date = March 2019 | pmid = 30865890 | pmc = 6418345 | doi = 10.1016/j.celrep.2019.02.044 }}</ref>

== Role as myokine ==

IL-6 is also considered a [[myokine]], a cytokine produced from muscle, which is elevated in response to muscle contraction.<ref>{{cite journal | vauthors = Febbraio MA, Pedersen BK | title = Contraction-induced myokine production and release: is skeletal muscle an endocrine organ? | journal = Exercise and Sport Sciences Reviews | volume = 33 | issue = 3 | pages = 114–119 | date = July 2005 | pmid = 16006818 | doi = 10.1097/00003677-200507000-00003 | s2cid = 26503323 | doi-access = free }}</ref> It is significantly elevated with exercise, and precedes the appearance of other cytokines in the circulation.  During exercise, it is thought to act in a hormone-like manner to mobilize extracellular substrates and/or augment substrate delivery.<ref name="pmid15772055">{{cite journal | vauthors = Petersen AM, Pedersen BK | title = The anti-inflammatory effect of exercise | journal = Journal of Applied Physiology | volume = 98 | issue = 4 | pages = 1154–1162 | date = April 2005 | pmid = 15772055 | doi = 10.1152/japplphysiol.00164.2004 | s2cid = 4776835 }}</ref>

Like in humans, there seems to be an increase in IL-6 expression in working muscle and plasma IL-6 concentration during exercise in rodents.<ref name="pmid11414667">{{cite journal | vauthors = Colbert LH, Davis JM, Essig DA, Ghaffar A, Mayer EP | title = Tissue expression and plasma concentrations of TNFalpha, IL-1beta, and IL-6 following treadmill exercise in mice | journal = International Journal of Sports Medicine | volume = 22 | issue = 4 | pages = 261–267 | date = May 2001 | pmid = 11414667 | doi = 10.1055/s-2001-13818 | s2cid = 260192304 }}</ref><ref name="pmid11018114">{{cite journal | vauthors = Jonsdottir IH, Schjerling P, Ostrowski K, Asp S, Richter EA, Pedersen BK | title = Muscle contractions induce interleukin-6 mRNA production in rat skeletal muscles | journal = The Journal of Physiology | volume = 528 Pt 1 | pages = 157–163 | date = October 2000 | issue = Pt 1 | pmid = 11018114 | pmc = 2270126 | doi = 10.1111/j.1469-7793.2000.00157.x }}</ref> Studies in mice with IL-6 gene knockout indicate that lack of IL-6 in mice affect exercise function.<ref name="pmid14988384">{{cite journal | vauthors = Fäldt J, Wernstedt I, Fitzgerald SM, Wallenius K, Bergström G, Jansson JO | title = Reduced exercise endurance in interleukin-6-deficient mice | journal = Endocrinology | volume = 145 | issue = 6 | pages = 2680–2686 | date = June 2004 | pmid = 14988384 | doi = 10.1210/en.2003-1319 | doi-access =  }}</ref>

It has been shown that the reduction of abdominal obesity by exercise in human adults can be reversed by the IL-6 receptor blocking antibody [[tocilizumab]]. Together with the findings that IL-6 prevents obesity,  stimulates [[lipolysis]] and is released from [[skeletal muscle]] during exercise, the tocilizumab finding indicates that IL-6 is required for exercise to reduce visceral adipose tissue mass.<ref name="pmid30595477">{{cite journal | vauthors = Wedell-Neergaard AS, Lang Lehrskov L, Christensen RH, Legaard GE, Dorph E, Larsen MK, Launbo N, Fagerlind SR, Seide SK, Nymand S, Ball M, Vinum N, Dahl CN, Henneberg M, Ried-Larsen M, Nybing JD, Christensen R, Rosenmeier JB, Karstoft K, Pedersen BK, Ellingsgaard H, Krogh-Madsen R | title = Exercise-Induced Changes in Visceral Adipose Tissue Mass Are Regulated by IL-6 Signaling: A Randomized Controlled Trial | journal = Cell Metabolism | volume = 29 | issue = 4 | pages = 844–855.e3 | date = April 2019 | pmid = 30595477 | doi = 10.1016/j.cmet.2018.12.007 | doi-access = free }}</ref>  Bone may be another organ affected by exercise induced IL-6, given that muscle-derived interleukin 6 has been reported to increase exercise capacity by signaling in osteoblasts.<ref name="pmid32078586">{{cite journal | vauthors = Chowdhury S, Schulz L, Palmisano B, Singh P, Berger JM, Yadav VK, Mera P, Ellingsgaard H, Hidalgo J, Brüning J, Karsenty G | title = Muscle-derived interleukin 6 increases exercise capacity by signaling in osteoblasts | journal = The Journal of Clinical Investigation | volume = 130 | issue = 6 | pages = 2888–2902 | date = June 2020 | pmid = 32078586 | pmc = 7260002 | doi = 10.1172/JCI133572 }}</ref>

IL-6 has extensive anti-inflammatory functions in its role as a [[myokine]]. IL-6 was the first myokine that was found to be secreted into the blood stream in response to muscle contractions.<ref name="pmid18923185">{{cite journal | vauthors = Pedersen BK, Febbraio MA | title = Muscle as an endocrine organ: focus on muscle-derived interleukin-6 | journal = Physiological Reviews | volume = 88 | issue = 4 | pages = 1379–1406 | date = October 2008 | pmid = 18923185 | doi = 10.1152/physrev.90100.2007 | s2cid = 12601630 }}</ref> Aerobic exercise provokes a systemic cytokine response, including, for example, IL-6, IL-1 receptor antagonist (IL-1ra), and IL-10. IL-6 was serendipitously discovered as a myokine because of the observation that it increased in an exponential fashion proportional to the length of exercise and the amount of muscle mass engaged in the exercise. It has been consistently demonstrated that the plasma concentration of IL-6 increases during muscular exercise. This increase is followed by the appearance of IL-1ra and the anti-inflammatory cytokine IL-10. In general, the cytokine response to exercise and sepsis differs with regard to TNF-α. Thus, the cytokine response to exercise is not preceded by an increase in plasma-TNF-α. Following exercise, the basal plasma IL-6 concentration may increase up to 100-fold, but less dramatic increases are more frequent. The exercise-induced increase of plasma IL-6 occurs in an exponential manner and the peak IL-6 level is reached at the end of the exercise or shortly thereafter. It is the combination of mode, intensity, and duration of the exercise that determines the magnitude of the exercise-induced increase of plasma IL-6.<ref name="pmid23897689">{{cite book |vauthors=Pedersen BK |chapter=Muscle as a secretory organ |title=Comprehensive Physiology |volume=3 |issue=3 |pages=1337–62 |date=July 2013 |pmid=23897689 |doi=10.1002/cphy.c120033 |isbn=9780470650714}}</ref>

IL-6 had previously been classified as a proinflammatory cytokine. Therefore, it was first thought that the exercise-induced IL-6 response was related to muscle damage.<ref name="pmid9130176">{{cite journal | vauthors = Bruunsgaard H, Galbo H, Halkjaer-Kristensen J, Johansen TL, MacLean DA, Pedersen BK | title = Exercise-induced increase in serum interleukin-6 in humans is related to muscle damage | journal = The Journal of Physiology | volume = 499 (Pt 3) | issue = 3 | pages = 833–841 | date = March 1997 | pmid = 9130176 | pmc = 1159298 | doi = 10.1113/jphysiol.1997.sp021972 }}</ref> However, it has become evident that [[Eccentric training|eccentric exercise]] is not associated with a larger increase in plasma IL-6 than exercise involving concentric "nondamaging" muscle contractions. This finding clearly demonstrates that muscle damage is not required to provoke an increase in plasma IL-6 during exercise. As a matter of fact, eccentric exercise may result in a delayed peak and a much slower decrease of plasma IL-6 during recovery.<ref name="pmid23897689" />

Recent work has shown that both upstream and downstream signalling pathways for IL-6 differ markedly between [[myocyte]]s and macrophages. It appears that unlike IL-6 signalling in macrophages, which is dependent upon activation of the NFκB signalling pathway, intramuscular IL-6 expression is regulated by a network of signalling cascades, including the [[Calcium in biology|{{Chem2|Ca(2+)}}]]/[[NFAT]] and glycogen/[[p38 mitogen-activated protein kinases|p38 MAPK]] pathways. Thus, when IL-6 is signalling in monocytes or macrophages, it creates a pro-inflammatory response, whereas IL-6 activation and signalling in muscle is totally
independent of a preceding TNF-response or NFκB activation, and is anti-inflammatory.<ref>{{cite journal | vauthors = Brandt C, Pedersen BK | title = The role of exercise-induced myokines in muscle homeostasis and the defense against chronic diseases | journal = Journal of Biomedicine & Biotechnology | volume = 2010 | pages = 520258 | year = 2010 | pmid = 20224659 | pmc = 2836182 | doi = 10.1155/2010/520258 | doi-access = free }}</ref>

IL-6, among an increasing number of other recently identified myokines, thus remains an important topic in myokine research. It appears in muscle tissue and in the circulation during exercise at levels up to one hundred times basal rates, as noted, and is seen as having a beneficial impact on health and bodily functioning when elevated in response to [[physical exercise]].<ref name="pmid23663276">{{cite journal | vauthors = Muñoz-Cánoves P, Scheele C, Pedersen BK, Serrano AL | title = Interleukin-6 myokine signaling in skeletal muscle: a double-edged sword? | journal = The FEBS Journal | volume = 280 | issue = 17 | pages = 4131–4148 | date = September 2013 | pmid = 23663276 | pmc = 4163639 | doi = 10.1111/febs.12338 }}</ref>

== Receptor ==

{{main|Interleukin-6 receptor}}
IL-6 signals through a cell-surface [[type I cytokine receptor]] complex consisting of the ligand-binding IL-6Rα chain ([[CD126]]), and the signal-transducing component [[gp130]] (also called CD130). CD130 is the common signal transducer for several cytokines including [[leukemia inhibitory factor]] (LIF), [[ciliary neurotropic factor]], [[oncostatin M]], [[interleukin 11|IL-11]] and [[cardiotrophin-1]], and is almost ubiquitously expressed in most tissues. In contrast, the expression of CD126 is restricted to certain tissues. As IL-6 interacts with its receptor, it triggers the gp130 and IL-6R proteins to form a complex, thus activating the receptor. These complexes bring together the [[intracellular]] regions of gp130 to initiate a signal transduction cascade through certain [[transcription factors]], [[Janus kinase]]s (JAKs) and Signal Transducers and Activators of Transcription ([[STAT protein|STATs]]).<ref>{{cite journal | vauthors = Heinrich PC, Behrmann I, Müller-Newen G, Schaper F, Graeve L | title = Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway | journal = The Biochemical Journal | volume = 334 (Pt 2) | issue = Pt 2 | pages = 297–314 | date = September 1998 | pmid = 9716487 | pmc = 1219691 | doi = 10.1042/bj3340297 }}</ref>

IL-6 is probably the best-studied of the cytokines that use [[gp130]], also known as IL-6 signal transducer (IL6ST),  in their signalling complexes. Other cytokines that signal through receptors containing gp130 are [[Interleukin 11]] (IL-11), [[Interleukin 27]] (IL-27), [[ciliary neurotrophic factor]] (CNTF), [[cardiotrophin-1]] (CT-1), [[CLCF1|cardiotrophin-like cytokine]] (CLC), [[leukemia inhibitory factor]] (LIF), [[oncostatin M]] (OSM), [[Kaposi's sarcoma-associated herpesvirus]] interleukin 6-like protein (KSHV-IL6).<ref>{{cite journal | vauthors = Kishimoto T, Akira S, Narazaki M, Taga T | title = Interleukin-6 family of cytokines and gp130 | journal = Blood | volume = 86 | issue = 4 | pages = 1243–1254 | date = August 1995 | pmid = 7632928 | doi = 10.1182/blood.V86.4.1243.bloodjournal8641243 | doi-access = free }}</ref> These cytokines are commonly referred to as the ''IL-6 like'' or ''gp130 utilising'' cytokines <ref>{{cite journal | vauthors = Heinrich PC, Behrmann I, Haan S, Hermanns HM, Müller-Newen G, Schaper F | title = Principles of interleukin (IL)-6-type cytokine signalling and its regulation | journal = The Biochemical Journal | volume = 374 | issue = Pt 1 | pages = 1–20 | date = August 2003 | pmid = 12773095 | pmc = 1223585 | doi = 10.1042/BJ20030407 }}</ref>

In addition to the membrane-bound receptor, a soluble form of IL-6R (sIL-6R) has been purified from human serum and urine. Many neuronal cells are unresponsive to stimulation by IL-6 alone, but differentiation and survival of neuronal cells can be mediated through the action of sIL-6R. The sIL-6R/IL-6 complex can stimulate neurites outgrowth and promote survival of neurons and, hence, may be important in nerve regeneration through remyelination.

==  Interactions ==

Interleukin-6 has been shown to [[Protein-protein interaction|interact]] with [[interleukin-6 receptor]],<ref name="pmid14557255">{{cite journal | vauthors = Schwantner A, Dingley AJ, Ozbek S, Rose-John S, Grötzinger J | title = Direct determination of the interleukin-6 binding epitope of the interleukin-6 receptor by NMR spectroscopy | journal = The Journal of Biological Chemistry | volume = 279 | issue = 1 | pages = 571–576 | date = January 2004 | pmid = 14557255 | doi = 10.1074/jbc.M311019200 | doi-access = free }}</ref><ref name="pmid12643274">{{cite journal | vauthors = Schuster B, Kovaleva M, Sun Y, Regenhard P, Matthews V, Grötzinger J, Rose-John S, Kallen KJ | title = Signaling of human ciliary neurotrophic factor (CNTF) revisited. The interleukin-6 receptor can serve as an alpha-receptor for CTNF | journal = The Journal of Biological Chemistry | volume = 278 | issue = 11 | pages = 9528–9535 | date = March 2003 | pmid = 12643274 | doi = 10.1074/jbc.M210044200 | doi-access =  free}}</ref><ref name="pmid2788034">{{cite journal | vauthors = Taga T, Hibi M, Hirata Y, Yamasaki K, Yasukawa K, Matsuda T, Hirano T, Kishimoto T | title = Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130 | journal = Cell | volume = 58 | issue = 3 | pages = 573–581 | date = August 1989 | pmid = 2788034 | doi = 10.1016/0092-8674(89)90438-8 | s2cid = 41245022 }}</ref> [[glycoprotein 130]],<ref name="pmid15989626">{{cite journal | vauthors = Kallen KJ, zum Büschenfelde KH, Rose-John S | title = The therapeutic potential of interleukin-6 hyperagonists and antagonists | journal = Expert Opinion on Investigational Drugs | volume = 6 | issue = 3 | pages = 237–266 | date = March 1997 | pmid = 15989626 | doi = 10.1517/13543784.6.3.237 }}</ref> and [[Galectin-3]].<ref>{{cite journal | vauthors = Gordon-Alonso M, Bruger AM, van der Bruggen P | title = Extracellular galectins as controllers of cytokines in hematological cancer | journal = Blood | volume = 132 | issue = 5 | pages = 484–491 | date = August 2018 | pmid = 29875102 | pmc = 6073326 | doi = 10.1182/blood-2018-04-846014 }}</ref>

There is considerable functional overlap and interaction between [[Substance P]] (SP), the natural ligand for the [[Tachykinin receptor 1|neurokinin type 1 receptor]] (NK1R, a mediator of immunomodulatory activity) and IL-6.

== Role in disease ==

IL-6 stimulates the inflammatory and auto-immune processes in many diseases such as [[multiple sclerosis]],<ref name="pmid28946890">{{cite journal | vauthors = Kong BS, Kim Y, Kim GY, Hyun JW, Kim SH, Jeong A, Kim HJ | title = Increased frequency of IL-6-producing non-classical monocytes in neuromyelitis optica spectrum disorder | journal = Journal of Neuroinflammation | volume = 14 | issue = 1 | pages = 191 | date = September 2017 | pmid = 28946890 | pmc = 5613387 | doi = 10.1186/s12974-017-0961-z | doi-access = free }}</ref> [[neuromyelitis optica spectrum disorder]] (NMOSD),<ref name="pmid28946890" /> [[diabetes]],<ref name="pmid16306329">{{cite journal | vauthors = Kristiansen OP, Mandrup-Poulsen T | title = Interleukin-6 and diabetes: the good, the bad, or the indifferent? | journal = Diabetes | volume = 54 | pages = S114–S124 | date = December 2005 | issue = Suppl 2 | pmid = 16306329 | doi = 10.2337/diabetes.54.suppl_2.S114 | doi-access = free }}</ref> [[atherosclerosis]],<ref name="pmid17684929">{{cite journal | vauthors = Dubiński A, Zdrojewicz Z | title = [The role of interleukin-6 in development and progression of atherosclerosis] | language = pl | journal = Polski Merkuriusz Lekarski | volume = 22 | issue = 130 | pages = 291–294 | date = April 2007 | pmid = 17684929 }}</ref> [[gastric cancer]],<ref>{{cite journal | vauthors = Yu B, de Vos D, Guo X, Peng S, Xie W, Peppelenbosch MP, Fu Y, Fuhler GM | title = IL-6 facilitates cross-talk between epithelial cells and tumor- associated macrophages in Helicobacter pylori-linked gastric carcinogenesis. | journal = Neoplasia | volume = 50 | pages = 100981 | date = April 2024 | pmid = 38422751 | pmc = 10912637 | doi = 10.1016/j.neo.2024.100981 | doi-access = free}}</ref> [[Major depressive disorder|depression]],<ref name="pmid 20015486">{{cite journal | vauthors = Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctôt KL | title = A meta-analysis of cytokines in major depression | journal = Biological Psychiatry | volume = 67 | issue = 5 | pages = 446–457 | date = March 2010 | pmid = 20015486 | doi = 10.1016/j.biopsych.2009.09.033 | s2cid = 230209 }}</ref> [[Alzheimer's disease]],<ref name="pmid 20692646">{{cite journal | vauthors = Swardfager W, Lanctôt K, Rothenburg L, Wong A, Cappell J, Herrmann N | title = A meta-analysis of cytokines in Alzheimer's disease | journal = Biological Psychiatry | volume = 68 | issue = 10 | pages = 930–941 | date = November 2010 | pmid = 20692646 | doi = 10.1016/j.biopsych.2010.06.012 | s2cid = 6544784 }}</ref> [[systemic lupus erythematosus]],<ref name="pmid15230289">{{cite journal | vauthors = Tackey E, Lipsky PE, Illei GG | title = Rationale for interleukin-6 blockade in systemic lupus erythematosus | journal = Lupus | volume = 13 | issue = 5 | pages = 339–343 | year = 2004 | pmid = 15230289 | pmc = 2014821 | doi = 10.1191/0961203304lu1023oa }}</ref> [[multiple myeloma]],<ref name="pmid10816321">{{cite journal | vauthors = Gadó K, Domján G, Hegyesi H, Falus A | title = Role of INTERLEUKIN-6 in the pathogenesis of multiple myeloma | journal = Cell Biology International | volume = 24 | issue = 4 | pages = 195–209 | year = 2000 | pmid = 10816321 | doi = 10.1006/cbir.2000.0497 | s2cid = 44820455 }}</ref> [[prostate cancer]],<ref name="pmid11312117">{{cite journal | vauthors = Smith PC, Hobisch A, Lin DL, Culig Z, Keller ET | title = Interleukin-6 and prostate cancer progression | journal = Cytokine & Growth Factor Reviews | volume = 12 | issue = 1 | pages = 33–40 | date = March 2001 | pmid = 11312117 | doi = 10.1016/S1359-6101(00)00021-6 }}</ref> [[Behçet's disease]],<ref name="pmid23257520">{{cite journal | vauthors = Hirohata S, Kikuchi H | title = Changes in biomarkers focused on differences in disease course or treatment in patients with neuro-Behçet's disease | journal = Internal Medicine | volume = 51 | issue = 24 | pages = 3359–3365 | date = Dec 2012 | pmid = 23257520 | doi = 10.2169/internalmedicine.51.8583 | doi-access = free }}</ref> [[rheumatoid arthritis]],<ref name="pmid16582692">{{cite journal | vauthors = Nishimoto N | title = Interleukin-6 in rheumatoid arthritis | journal = Current Opinion in Rheumatology | volume = 18 | issue = 3 | pages = 277–281 | date = May 2006 | pmid = 16582692 | doi = 10.1097/01.bor.0000218949.19860.d1 | s2cid = 20188179 }}</ref> and intracerebral hemorrhage.<ref>{{cite journal | vauthors = Zhu H, Wang Z, Yu J, Yang X, He F, Liu Z, Che F, Chen X, Ren H, Hong M, Wang J | title = Role and mechanisms of cytokines in the secondary brain injury after intracerebral hemorrhage | journal = Progress in Neurobiology | volume = 178 | pages = 101610 | date = July 2019 | pmid = 30923023 | doi = 10.1016/j.pneurobio.2019.03.003 | s2cid = 85495400 }}</ref>

Hence, there is an interest in developing [[anti-IL-6]] agents as therapy against many of these diseases.<ref name="pmid16083340">{{cite journal | vauthors = Barton BE | title = Interleukin-6 and new strategies for the treatment of cancer, hyperproliferative diseases and paraneoplastic syndromes | journal = Expert Opinion on Therapeutic Targets | volume = 9 | issue = 4 | pages = 737–752 | date = August 2005 | pmid = 16083340 | doi = 10.1517/14728222.9.4.737 | s2cid = 45421426 }}</ref><ref name="pmid16899109">{{cite journal | vauthors = Smolen JS, Maini RN | title = Interleukin-6: a new therapeutic target | journal = Arthritis Research & Therapy | volume = 8 | issue = Suppl 2 | pages = S5 | year = 2006 | pmid = 16899109 | pmc = 3226077 | doi = 10.1186/ar1969 | doi-access = free }}</ref> The first such is [[tocilizumab]], which has been approved for [[rheumatoid arthritis]],<ref name="EmeryKeystone2008">{{cite journal | vauthors = Emery P, Keystone E, Tony HP, Cantagrel A, van Vollenhoven R, Sanchez A, Alecock E, Lee J, Kremer J | title = IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial | journal = Annals of the Rheumatic Diseases | volume = 67 | issue = 11 | pages = 1516–1523 | date = November 2008 | pmid = 18625622 | pmc = 3811149 | doi = 10.1136/ard.2008.092932 }}</ref> [[Castleman's disease]]<ref name="Nishimoto2005">{{cite journal | vauthors = Nishimoto N, Kanakura Y, Aozasa K, Johkoh T, Nakamura M, Nakano S, Nakano N, Ikeda Y, Sasaki T, Nishioka K, Hara M, Taguchi H, Kimura Y, Kato Y, Asaoku H, Kumagai S, Kodama F, Nakahara H, Hagihara K, Yoshizaki K, Kishimoto T | title = Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease | journal = Blood | volume = 106 | issue = 8 | pages = 2627–2632 | date = October 2005 | pmid = 15998837 | doi = 10.1182/blood-2004-12-4602 | doi-access = free }}</ref> and [[systemic juvenile idiopathic arthritis]].<ref name="YokotaImagawa2008">{{cite journal | vauthors = Yokota S, Imagawa T, Mori M, Miyamae T, Aihara Y, Takei S, Iwata N, Umebayashi H, Murata T, Miyoshi M, Tomiita M, Nishimoto N, Kishimoto T | title = Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial | journal = Lancet | volume = 371 | issue = 9617 | pages = 998–1006 | date = March 2008 | pmid = 18358927 | doi = 10.1016/S0140-6736(08)60454-7 | s2cid = 21554759 }}</ref>  Others are in clinical trials.<ref name=N-2013>[http://www.nature.com/nm/journal/v19/n10/full/nm1013-1193.html First IL-6–blocking drug nears approval for rare blood disorder], Nature Medicine, October 7, 2013</ref> It has been observed that genetic inactivation of ZCCHC 6 suppresses IL‐6 expression and reduces the severity of experimental osteoarthritis in Mice.<ref>{{Cite journal |date=April 2019 |title=Genetic Inactivation of ZCCHC6 Suppresses Interleukin-6 Expression and Reduces the Severity of Experimental Osteoarthritis in Mice |journal=Arthritis & Rheumatology |volume=71 |issue=4 |pages=583–593 |doi=10.1002/art.40751 |issn=2326-5205 |pmc=6438766 |pmid=30302948|vauthors=Ansari MY, Khan NM, Ahmad N, Green J, Novak K, Haqqi TM}}</ref> Some plant derived small molecule such as Butein have been reported to inhibit IL-6 expression in IL-1β stimulated human chondrocytes.<ref>{{Cite journal | date=2018 |title=Butein Activates Autophagy Through AMPK/TSC2/ULK1/mTOR Pathway to Inhibit IL-6 Expression in IL-1β Stimulated Human Chondrocytes |url= |journal=Cellular Physiology and Biochemistry: International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology |volume=49 |issue=3 |pages=932–946 |doi=10.1159/000493225 |issn=1421-9778 |pmid=30184535|s2cid=52166938|vauthors=Ansari MY, Ahmad N, Haqqi TM |doi-access=free }}</ref>

===Liver diseases===
Since IL-6 is a well-known pleiotropic molecule, it plays a dual role in the pathogenesis of liver diseases. While it is necessary for promoting [[liver regeneration]],<ref>{{cite journal | vauthors = Gao B, Ahmad MF, Nagy LE, Tsukamoto H | title = Inflammatory pathways in alcoholic steatohepatitis | journal = Journal of Hepatology | volume = 70 | issue = 2 | pages = 249–259 | date = February 2019 | pmid = 30658726 | pmc = 6361545 | doi = 10.1016/j.jhep.2018.10.023 }}</ref> IL-6 is also a highly recognized marker of [[systemic inflammation]] and its association with mortality in [[liver disease]]s has been reported by multiple studies.<ref>{{cite journal | vauthors = Remmler J, Schneider C, Treuner-Kaueroff T, Bartels M, Seehofer D, Scholz M, Berg T, Kaiser T | title = Increased Level of Interleukin 6 Associates With Increased 90-Day and 1-Year Mortality in Patients With End-Stage Liver Disease | journal = Clinical Gastroenterology and Hepatology | volume = 16 | issue = 5 | pages = 730–737 | date = May 2018 | pmid = 28919544 | doi = 10.1016/j.cgh.2017.09.017 | s2cid = 4408167 }}</ref><ref>{{cite journal | vauthors = Zhou C, Zhang N, He TT, Wang Y, Wang LF, Sun YQ, Jing J, Zhang JJ, Fu SN, Wang X, Liang XX, Li X, Gong M, Li J | title = High levels of serum interleukin-6 increase mortality of hepatitis B virus-associated acute-on-chronic liver failure | journal = World Journal of Gastroenterology | volume = 26 | issue = 30 | pages = 4479–4488 | date = August 2020 | pmid = 32874059 | pmc = 7438191 | doi = 10.3748/wjg.v26.i30.4479 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Sheron N, Bird G, Goka J, Alexander G, Williams R | title = Elevated plasma interleukin-6 and increased severity and mortality in alcoholic hepatitis | journal = Clinical and Experimental Immunology | volume = 84 | issue = 3 | pages = 449–453 | date = June 1991 | pmid = 2044224 | pmc = 1535433 }}</ref><ref>{{cite journal | vauthors = Arroyo V, Angeli P, Moreau R, Jalan R, Clària J, Trebicka J, Fernández J, Gustot T, Caraceni P, Bernardi M | title = The systemic inflammation hypothesis: Towards a new paradigm of acute decompensation and multiorgan failure in cirrhosis | journal = Journal of Hepatology | volume = 74 | issue = 3 | pages = 670–685 | date = March 2021 | pmid = 33301825 | doi = 10.1016/j.jhep.2020.11.048 | hdl-access = free | hdl = 2445/175350 }}</ref><ref name=":0">{{cite journal | vauthors = Tornai D, Mitchell M, McClain CJ, Dasarathy S, McCullough A, Radaeva S, Kroll-Desrosiers A, Lee J, Barton B, Szabo G | title = A novel score of IL-13 and age predicts 90-day mortality in severe alcohol-associated hepatitis: A multicenter plasma biomarker analysis | journal = Hepatology Communications | volume = 7 | issue = 12 | date = December 2023 | pmid = 37994498 | pmc = 10666984 | doi = 10.1097/HC9.0000000000000296 }}</ref> In patients with severe [[Alcoholic hepatitis|alcohol-associated hepatitis]], IL-6 showed the most robust elevation among inflammatory cytokines compared to healthy controls with a further increase in non-survivors. In these patients, IL-6 was a predictor of short-term (28- and 90-day) mortality.<ref name=":0" />

===Rheumatoid arthritis===
The first FDA approved [[anti-IL-6]] treatment was for rheumatoid arthritis.

=== Cancer ===
[[Anti-IL-6]] therapy was initially developed for treatment of [[autoimmune diseases]], but due to the role of IL-6 in chronic inflammation, IL-6 blockade was also evaluated for cancer treatment.<ref>{{cite journal | vauthors = Korneev KV, Atretkhany KN, Drutskaya MS, Grivennikov SI, Kuprash DV, Nedospasov SA | title = TLR-signaling and proinflammatory cytokines as drivers of tumorigenesis | journal = Cytokine | volume = 89 | pages = 127–135 | date = January 2017 | pmid = 26854213 | doi = 10.1016/j.cyto.2016.01.021 }}</ref><ref name="AnestakisPetanidis2015">{{cite journal | vauthors = Anestakis D, Petanidis S, Kalyvas S, Nday CM, Tsave O, Kioseoglou E, Salifoglou A | title = Mechanisms and applications of interleukins in cancer immunotherapy | journal = International Journal of Molecular Sciences | volume = 16 | issue = 1 | pages = 1691–1710 | date = January 2015 | pmid = 25590298 | pmc = 4307328 | doi = 10.3390/ijms16011691 | doi-access = free }}</ref><ref name="Bone marrow-confined IL-6 signaling">{{cite journal | vauthors = Mei Y, Ren K, Liu Y, Ma A, Xia Z, Han X, Li E, Tariq H, Bao H, Xie X, Zou C, Zhang D, Li Z, Dong L, Verma A, Lu X, Abaza Y, Altman JK, Sukhanova M, Yang J, Ji P | title = Bone marrow-confined IL-6 signaling mediates the progression of myelodysplastic syndromes to acute myeloid leukemia | journal = The Journal of Clinical Investigation | volume = 132 | issue = 17 | pages = e152673 | date = September 2022 | pmid = 35900794 | pmc = 9435651 | doi = 10.1172/JCI152673 }}</ref> IL-6 was seen to have roles in tumor microenvironment regulation,<ref name="LiMo2012">{{cite journal | vauthors = Li J, Mo HY, Xiong G, Zhang L, He J, Huang ZF, Liu ZW, Chen QY, Du ZM, Zheng LM, Qian CN, Zeng YX | title = Tumor microenvironment macrophage inhibitory factor directs the accumulation of interleukin-17-producing tumor-infiltrating lymphocytes and predicts favorable survival in nasopharyngeal carcinoma patients | journal = The Journal of Biological Chemistry | volume = 287 | issue = 42 | pages = 35484–35495 | date = October 2012 | pmid = 22893706 | pmc = 3471767 | doi = 10.1074/jbc.M112.367532 | doi-access = free }}</ref><ref name="Bone marrow-confined IL-6 signaling"/> production of [[breast cancer]] stem cell-like cells,<ref name="Yuan2011">{{cite journal | vauthors = Xie G, Yao Q, Liu Y, Du S, Liu A, Guo Z, Sun A, Ruan J, Chen L, Ye C, Yuan Y | title = IL-6-induced epithelial-mesenchymal transition promotes the generation of breast cancer stem-like cells analogous to mammosphere cultures | journal = International Journal of Oncology | volume = 40 | issue = 4 | pages = 1171–1179 | date = April 2012 | pmid = 22134360 | pmc = 3584811 | doi = 10.3892/ijo.2011.1275 }}</ref> metastasis through down-regulation of E-cadherin,<ref name="MiaoLiu2014">{{cite journal | vauthors = Miao JW, Liu LJ, Huang J | title = Interleukin-6-induced epithelial-mesenchymal transition through signal transducer and activator of transcription 3 in human cervical carcinoma | journal = International Journal of Oncology | volume = 45 | issue = 1 | pages = 165–176 | date = July 2014 | pmid = 24806843 | doi = 10.3892/ijo.2014.2422 | doi-access = free }}</ref> and alteration of DNA methylation in oral cancer.<ref name="GascheHoffmann2011">{{cite journal | vauthors = Gasche JA, Hoffmann J, Boland CR, Goel A | title = Interleukin-6 promotes tumorigenesis by altering DNA methylation in oral cancer cells | journal = International Journal of Cancer | volume = 129 | issue = 5 | pages = 1053–1063 | date = September 2011 | pmid = 21710491 | pmc = 3110561 | doi = 10.1002/ijc.25764 }}</ref>

Advanced/[[metastatic cancer]] patients have higher levels of IL-6 in their blood.<ref name="urlMedscape.com Log In">{{cite web |url=http://www.medscape.com/viewarticle/537309 |title=Cancer Patients Typically Have Increased Interleukin-6 Levels |date=2006-06-26 |work=American Society of Clinical Oncology 2006 Annual Meeting, Abstracts 8632 and 8633 |publisher=Medscape.com}}</ref> One example of this is [[pancreatic cancer]], with noted elevation of IL-6 present in patients correlating with poor survival rates.<ref name="BelloneSmirne2005">{{cite journal | vauthors = Bellone G, Smirne C, Mauri FA, Tonel E, Carbone A, Buffolino A, Dughera L, Robecchi A, Pirisi M, Emanuelli G | title = Cytokine expression profile in human pancreatic carcinoma cells and in surgical specimens: implications for survival | journal = Cancer Immunology, Immunotherapy | volume = 55 | issue = 6 | pages = 684–698 | date = June 2006 | pmid = 16094523 | doi = 10.1007/s00262-005-0047-0 | pmc = 11031060 | s2cid = 11019678 }}</ref>

=== Diseases ===

====Enterovirus 71====
High IL-6 levels are associated with the development of [[encephalitis]] in children and immunodeficient [[Laboratory mouse|mouse models]] infected with [[Enterovirus 71]]; this highly contagious virus normally causes a milder illness called [[Hand, foot, and mouth disease]] but can cause life-threatening encephalitis in some cases. EV71 patients with a certain [[gene polymorphism]] in IL-6 also appear to be more susceptible to developing encephalitis.

=== Epigenetic modifications  ===

IL-6 has been shown to lead to several neurological diseases through its impact on [[epigenetics|epigenetic]] modification within the brain.<ref name="pmid17913903">{{cite journal | vauthors = Smith SE, Li J, Garbett K, Mirnics K, Patterson PH | title = Maternal immune activation alters fetal brain development through interleukin-6 | journal = The Journal of Neuroscience | volume = 27 | issue = 40 | pages = 10695–10702 | date = October 2007 | pmid = 17913903 | pmc = 2387067 | doi = 10.1523/JNEUROSCI.2178-07.2007 }}</ref><ref name="pmid19029285">{{cite journal | vauthors = Kundakovic M, Chen Y, Guidotti A, Grayson DR | title = The reelin and GAD67 promoters are activated by epigenetic drugs that facilitate the disruption of local repressor complexes | journal = Molecular Pharmacology | volume = 75 | issue = 2 | pages = 342–354 | date = February 2009 | pmid = 19029285 | pmc = 2684898 | doi = 10.1124/mol.108.051763 }}</ref> IL-6 activates the [[Phosphoinositide 3-kinase]] (PI3K) pathway, and a downstream target of this pathway is the [[AKT|protein kinase B]] (PKB) (Hodge et al., 2007). IL-6 activated PKB can phosphorylate the nuclear localization signal on [[DNMT1|DNA methyltransferase-1]] (DNMT1).<ref name="pmid18204201">{{cite journal | vauthors = Hodge DR, Cho E, Copeland TD, Guszczynski T, Yang E, Seth AK, Farrar WL | title = IL-6 enhances the nuclear translocation of DNA cytosine-5-methyltransferase 1 (DNMT1) via phosphorylation of the nuclear localization sequence by the AKT kinase | journal = Cancer Genomics & Proteomics | volume = 4 | issue = 6 | pages = 387–398 | year = 2007 | pmid = 18204201 }}</ref> This phosphorylation causes movement of DNMT1 to the nucleus, where it can be transcribed.<ref name="pmid18204201"/> DNMT1 recruits other DNMTs, including DNMT3A and DNMT3B, which, as a complex, recruit [[HDAC1]].<ref name="pmid19029285"/> This complex adds methyl groups to [[CpG islands]] on gene promoters, repressing the chromatin structure surrounding the DNA sequence and inhibiting transcriptional machinery from accessing the gene to induce transcription.<ref name="pmid19029285"/> Increased IL-6, therefore, can hypermethylate DNA sequences and subsequently decrease gene expression through its effects on DNMT1 expression.<ref name="pmid20354000">{{cite journal | vauthors = Foran E, Garrity-Park MM, Mureau C, Newell J, Smyrk TC, Limburg PJ, Egan LJ | title = Upregulation of DNA methyltransferase-mediated gene silencing, anchorage-independent growth, and migration of colon cancer cells by interleukin-6 | journal = Molecular Cancer Research | volume = 8 | issue = 4 | pages = 471–481 | date = April 2010 | pmid = 20354000 | doi = 10.1158/1541-7786.MCR-09-0496 | doi-access = free }}</ref>

==== Schizophrenia ====

The induction of epigenetic modification by IL-6 has been proposed as a mechanism in the pathology of schizophrenia through the hypermethylation and repression of the [[Glutamate decarboxylase|GAD67]] promoter.<ref name="pmid19029285"/> This hypermethylation may potentially lead to the decreased GAD67 levels seen in the brains of people with schizophrenia.<ref name="pmid11074872">{{cite journal | vauthors = Guidotti A, Auta J, Davis JM, Di-Giorgi-Gerevini V, Dwivedi Y, Grayson DR, Impagnatiello F, Pandey G, Pesold C, Sharma R, Uzunov D, Costa E, DiGiorgi Gerevini V | title = Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study | journal = Archives of General Psychiatry | volume = 57 | issue = 11 | pages = 1061–1069 | date = November 2000 | pmid = 11074872 | doi = 10.1001/archpsyc.57.11.1061 | doi-access =  }}</ref> GAD67 may be involved in the pathology of schizophrenia through its effect on [[gamma-Aminobutyric acid|GABA]] levels and on [[neural oscillation]]s.<ref name="pmid22806213">{{cite journal | vauthors = Gandal MJ, Sisti J, Klook K, Ortinski PI, Leitman V, Liang Y, Thieu T, Anderson R, Pierce RC, Jonak G, Gur RE, Carlson G, Siegel SJ | title = GABAB-mediated rescue of altered excitatory-inhibitory balance, gamma synchrony and behavioral deficits following constitutive NMDAR-hypofunction | journal = Translational Psychiatry | volume = 2 | issue = 7 | pages = e142 | date = July 2012 | pmid = 22806213 | pmc = 3410621 | doi = 10.1038/tp.2012.69 }}</ref> Neural oscillations occur when inhibitory GABAergic neurons fire synchronously and cause inhibition of a multitude of target excitatory neurons at the same time, leading to a cycle of inhibition and disinhibition.<ref name="pmid22806213"/> These neural oscillations are impaired in schizophrenia, and these alterations may be responsible for both positive and negative symptoms of schizophrenia.<ref name="pmid20087360">{{cite journal | vauthors = Uhlhaas PJ, Singer W | title = Abnormal neural oscillations and synchrony in schizophrenia | journal = Nature Reviews. Neuroscience | volume = 11 | issue = 2 | pages = 100–113 | date = February 2010 | pmid = 20087360 | doi = 10.1038/nrn2774 | s2cid = 205505539 }}</ref>

==== Aging ====
IL-6 is commonly found in the [[senescence-associated secretory phenotype]] (SASP) factors secreted by [[Cellular senescence|senescent cells]] (a toxic cell-type that increases with [[Ageing|aging]]).<ref name="pmid19053174">{{cite journal | vauthors = Coppé JP, Patil CK, Rodier F, Sun Y, Muñoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J | title = Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor | journal = PLOS Biology | volume = 6 | issue = 12 | pages = 2853–2868 | date = December 2008 | pmid = 19053174 | pmc = 2592359 | doi = 10.1371/journal.pbio.0060301 | doi-access = free }}</ref><ref name="pmid28729727">{{cite journal | vauthors = Childs BG, Gluscevic M, Baker DJ, Laberge RM, Marquess D, Dananberg J, van Deursen JM | title = Senescent cells: an emerging target for diseases of ageing | journal = Nature Reviews. Drug Discovery | volume = 16 | issue = 10 | pages = 718–735 | date = October 2017 | pmid = 28729727 | pmc = 5942225 | doi = 10.1038/nrd.2017.116 }}</ref> Cancer (a disease that increases with age) invasiveness is promoted primarily though the actions of the SASP factors [[metalloproteinase]], [[chemokine]], IL-6, and [[interleukin 8]] (IL-8).<ref name="pmid30526772">{{cite journal | vauthors = Kim YH, Park TJ | title = Cellular senescence in cancer | journal = BMB Reports | volume = 52 | issue = 1 | pages = 42–46 | date = January 2019 | pmid = 30526772 | pmc = 6386235 | doi = 10.5483/BMBRep.2019.52.1.295 }}</ref><ref name="pmid19053174" /> IL-6 and IL-8 are the most [[Molecular evolution#Protein evolution|conserved]] and robust features of SASP.<ref name="pmid32467649">{{cite journal | vauthors = Partridge L, Fuentealba M, Kennedy BK | title = The quest to slow ageing through drug discovery | journal = Nature Reviews. Drug Discovery | volume = 19 | issue = 8 | pages = 513–532 | date = August 2020 | pmid = 32467649 | doi = 10.1038/s41573-020-0067-7 | s2cid = 218912510 | url = https://discovery.ucl.ac.uk/id/eprint/10101648/ | hdl = 21.11116/0000-0007-868D-3 | hdl-access = free }}</ref>

'''Myelodysplastic Syndromes'''

IL-6 receptor was found upregulated in high-risk MDS patients. The inhibition of IL-6 signaling pathway can significantly ameliorate the clonogenicity of MDS hematopoietic stem and progenitor cells (HSPCs), but have undetectable effect on normal HSPCs.<ref name="Bone marrow-confined IL-6 signaling"/>

==== Depression and major depressive disorder ====
{{See also|Epigenetics of depression#Brain-derived neurotrophic factor, Epigenetics of schizophrenia#Methylation of BDNF}}
The epigenetic effects IL-6 have also been implicated in the pathology of [[Depression (mood)|depression]]. The effects of IL-6 on depression are mediated through the repression of [[brain-derived neurotrophic factor]] (BDNF) expression in the brain; DNMT1 hypermethylates the BDNF promoter and reduces BDNF levels.<ref name="pmid18536530">{{cite journal | vauthors = Sharma RP, Tun N, Grayson DR | title = Depolarization induces downregulation of DNMT1 and DNMT3a in primary cortical cultures | journal = Epigenetics | volume = 3 | issue = 2 | pages = 74–80 | year = 2008 | pmid = 18536530 | doi = 10.4161/epi.3.2.6103 | doi-access = free }}</ref> Altered BDNF function has been implicated in depression,<ref name="pmid16343697">{{cite journal | vauthors = Hwang JP, Tsai SJ, Hong CJ, Yang CH, Lirng JF, Yang YM | title = The Val66Met polymorphism of the brain-derived neurotrophic-factor gene is associated with geriatric depression | journal = Neurobiology of Aging | volume = 27 | issue = 12 | pages = 1834–1837 | date = December 2006 | pmid = 16343697 | doi = 10.1016/j.neurobiolaging.2005.10.013 | s2cid = 23626890 }}</ref> which is likely due to epigenetic modification following IL-6 upregulation.<ref name="pmid18536530"/> BDNF is a neurotrophic factor implicated in spine formation, density, and morphology on neurons.<ref name="pmid15882774">{{cite journal | vauthors = Ethell IM, Pasquale EB | title = Molecular mechanisms of dendritic spine development and remodeling | journal = Progress in Neurobiology | volume = 75 | issue = 3 | pages = 161–205 | date = February 2005 | pmid = 15882774 | doi = 10.1016/j.pneurobio.2005.02.003 | s2cid = 24889257 }}</ref> Downregulation of BDNF, therefore, may cause decreased connectivity in the brain. Depression is marked by altered connectivity, in particular between the [[anterior cingulate cortex]] and several other limbic areas, such as the [[hippocampus]].<ref name="pmid17210143">{{cite journal |author4-link=Gary H. Glover | vauthors = Greicius MD, Flores BH, Menon V, Glover GH, Solvason HB, Kenna H, Reiss AL, Schatzberg AF | title = Resting-state functional connectivity in major depression: abnormally increased contributions from subgenual cingulate cortex and thalamus | journal = Biological Psychiatry | volume = 62 | issue = 5 | pages = 429–437 | date = September 2007 | pmid = 17210143 | pmc = 2001244 | doi = 10.1016/j.biopsych.2006.09.020 }}</ref> The anterior cingulate cortex is responsible for detecting incongruences between expectation and perceived experience.<ref name="pmid16819523">{{cite journal | vauthors = Somerville LH, Heatherton TF, Kelley WM | title = Anterior cingulate cortex responds differentially to expectancy violation and social rejection | journal = Nature Neuroscience | volume = 9 | issue = 8 | pages = 1007–1008 | date = August 2006 | pmid = 16819523 | doi = 10.1038/nn1728 | s2cid = 35224855 }}</ref> Altered connectivity of the anterior cingulate cortex in depression, therefore, may cause altered emotions following certain experiences, leading to depressive reactions.<ref name="pmid16819523"/> This altered connectivity is mediated by IL-6 and its effect on epigenetic regulation of BDNF.<ref name="pmid18536530"/>

Additional preclinical and clinical data, suggest that [[Substance P]] [SP] and IL-6 may act in concert to promote major depression. SP, a hybrid neurotransmitter-cytokine, is co-transmitted with BDNF through paleo-spinothalamic circuitry from the periphery with collaterals into key areas of the limbic system. However, both IL6 and SP mitigate expression of BDNF in brain regions associated with negative affect and memory. SP and IL6 both relax tight junctions of the blood brain barrier, such that effects seen in fMRI experiments with these molecules may be a bidirectional mix of neuronal, glial, capillary, synaptic, paracrine, or endocrine-like effects. At the cellular level, SP is noted to increase expression of interleukin-6 (IL-6) through PI-3K, p42/44 and p38 MAP kinase pathways. Data suggest that nuclear translocation of NF-κB regulates IL-6 overexpression in SP-stimulated cells.<ref name="pmid14654230">{{cite journal | vauthors = Azzolina A, Bongiovanni A, Lampiasi N | title = Substance P induces TNF-alpha and IL-6 production through NF kappa B in peritoneal mast cells | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1643 | issue = 1–3 | pages = 75–83 | date = December 2003 | pmid = 14654230 | doi = 10.1016/j.bbamcr.2003.09.003 | doi-access =  }}</ref> This is of key interest as: 1) a meta-analysis indicates an association of major depressive disorder, C-reactive protein and IL6 plasma concentrations,<ref name="pmid26065825">{{cite journal | vauthors = Haapakoski R, Mathieu J, Ebmeier KP, Alenius H, Kivimäki M | title = Cumulative meta-analysis of interleukins 6 and 1β, tumour necrosis factor α and C-reactive protein in patients with major depressive disorder | journal = Brain, Behavior, and Immunity | volume = 49 | pages = 206–215 | date = October 2015 | pmid = 26065825 | pmc = 4566946 | doi = 10.1016/j.bbi.2015.06.001 }}</ref> 2) NK1R antagonists [five molecules] studied by 3 independent groups in over 2000 patients from 1998 to 2013 validate the mechanism as dose-related, fully effective antidepressant,  with a unique safety profile.<ref name="pmid23539641">{{cite journal | vauthors = Ratti E, Bettica P, Alexander R, Archer G, Carpenter D, Evoniuk G, Gomeni R, Lawson E, Lopez M, Millns H, Rabiner EA, Trist D, Trower M, Zamuner S, Krishnan R, Fava M | title = Full central neurokinin-1 receptor blockade is required for efficacy in depression: evidence from orvepitant clinical studies | journal = Journal of Psychopharmacology | volume = 27 | issue = 5 | pages = 424–434 | date = May 2013 | pmid = 23539641 | doi = 10.1177/0269881113480990 | s2cid = 6523822 }}</ref><ref name="pmid9733503">{{cite journal | vauthors = Kramer MS, Cutler N, Feighner J, Shrivastava R, Carman J, Sramek JJ, Reines SA, Liu G, Snavely D, Wyatt-Knowles E, Hale JJ, Mills SG, MacCoss M, Swain CJ, Harrison T, Hill RG, Hefti F, Scolnick EM, Cascieri MA, Chicchi GG, Sadowski S, Williams AR, Hewson L, Smith D, Carlson EJ, Hargreaves RJ, Rupniak NM | title = Distinct mechanism for antidepressant activity by blockade of central substance P receptors | journal = Science | volume = 281 | issue = 5383 | pages = 1640–1645 | date = September 1998 | pmid = 9733503 | doi = 10.1126/science.281.5383.1640 | bibcode = 1998Sci...281.1640K }}</ref> [[Aprepitant#Major Depression|(see Summary of NK1RAs in Major Depression)]], 3) the preliminary observation that plasma concentrations of IL6 are elevated in depressed patients with cancer,<ref name="pmid11481159">{{cite journal | vauthors = Musselman DL, Miller AH, Porter MR, Manatunga A, Gao F, Penna S, Pearce BD, Landry J, Glover S, McDaniel JS, Nemeroff CB | title = Higher than normal plasma interleukin-6 concentrations in cancer patients with depression: preliminary findings | journal = The American Journal of Psychiatry | volume = 158 | issue = 8 | pages = 1252–1257 | date = August 2001 | pmid = 11481159 | doi = 10.1176/appi.ajp.158.8.1252 }}</ref> and 4) selective NK1RAs may eliminate endogenous SP stress-induced augmentation of IL-6 secretion pre-clinically.<ref name="pmid8642417">{{cite journal | vauthors = Zhu GF, Chancellor-Freeland C, Berman AS, Kage R, Leeman SE, Beller DI, Black PH | title = Endogenous substance P mediates cold water stress-induced increase in interleukin-6 secretion from peritoneal macrophages | journal = The Journal of Neuroscience | volume = 16 | issue = 11 | pages = 3745–3752 | date = June 1996 | pmid = 8642417 | pmc = 6578844 | doi = 10.1523/JNEUROSCI.16-11-03745.1996 }}</ref> These and many other reports suggest that a clinical study of a neutralizing IL-6 biological or drug based antagonist is likely warranted in patients with major depressive disorder, with or without co-morbid chronic inflammatory based illnesses; that the combination of NK1RAs and IL6 blockers may represent a new, potentially biomarkable approach to major depression, and possibly [[bipolar disorder]].

The IL-6 antibody [[sirukumab]] underwent clinical trials for adjunctive treatment of [[major depressive disorder]] in 2015–2018,<ref>{{ClinicalTrialsGov|NCT02473289|An Efficacy and Safety Study of Sirukumab in Participants With Major Depressive Disorder.}}</ref> but this research has been discontinued.<ref>{{cite web | title = Sirukumab - Janssen Biotech | url = http://adisinsight.springer.com/drugs/800026523 | work = AdisInsight | publisher = Springer Nature Switzerland AG }}</ref>

===Asthma===
Obesity is a known risk factor in the development of severe asthma. Recent data suggests that the inflammation associated with obesity, potentially mediated by IL-6, plays a role in causing poor lung function and increased risk for developing asthma exacerbations.<ref>{{cite journal | vauthors = Peters MC, McGrath KW, Hawkins GA, Hastie AT, Levy BD, Israel E, Phillips BR, Mauger DT, Comhair SA, Erzurum SC, Johansson MW, Jarjour NN, Coverstone AM, Castro M, Holguin F, Wenzel SE, Woodruff PG, Bleecker ER, Fahy JV | title = Plasma interleukin-6 concentrations, metabolic dysfunction, and asthma severity: a cross-sectional analysis of two cohorts | journal = The Lancet. Respiratory Medicine | volume = 4 | issue = 7 | pages = 574–584 | date = July 2016 | pmid = 27283230 | pmc = 5007068 | doi = 10.1016/S2213-2600(16)30048-0 }}</ref>

== Protein superfamily ==
Interleukin is the main member of the IL-6 superfamily ({{Pfam|PF00489}}), which also includes [[Granulocyte colony-stimulating factor|G-CSF]], [[Interleukin-23|IL23A]], and [[CLCF1]]. A viral version of IL6 is found in [[Kaposi's sarcoma-associated herpesvirus]].<ref>{{cite journal | vauthors = Suthaus J, Stuhlmann-Laeisz C, Tompkins VS, Rosean TR, Klapper W, Tosato G, Janz S, Scheller J, Rose-John S | title = HHV-8-encoded viral IL-6 collaborates with mouse IL-6 in the development of multicentric Castleman disease in mice | journal = Blood | volume = 119 | issue = 22 | pages = 5173–5181 | date = May 2012 | pmid = 22490805 | pmc = 3370672 | doi = 10.1182/blood-2011-09-377705 }}</ref>

== See also ==
*[[Ziltivekimab]], a fully human monoclonal antibody against interleukin 6.<!--- Editor comment: Place here for now. Expert editor may wish to move elsewhere within the article. --->

== References ==
{{Reflist}}

== External links ==
*[http://www.cancerindex.org/geneweb/IL6.htm IL-6 expression in various cancers]
* {{PDBe-KB2|P05231|Human Interleukin-6}}
* {{PDBe-KB2|P08505|Mouse Interleukin-6}}

{{PDB Gallery|geneid=3569}}
{{Interleukins}}
{{Neurotrophic factors}}
{{Interleukin receptor modulators}}
{{Longevity}}

[[Category:Interleukins]]
[[Category:Osaka University research]]
[[Category:Neurotrophic factors]]