79.141.40.227: /* Clinical implications */

2025-05-06T14:12:53Z

Clinical implications

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{{Short description|Type of signaling molecule}}
An '''inflammatory cytokine''' or '''proinflammatory cytokine''' is a type of signaling molecule (a [[cytokine]]) that is secreted from immune cells like [[helper T cell]]s ('''Th''') and [[macrophage]]s, and certain other cell types that promote [[inflammation]]. They include [[interleukin-1]] (IL-1), [[interleukin 6|IL-6]], [[interleukin 12|IL-12]], and [[interleukin 18|IL-18]], [[tumor necrosis factor|tumor necrosis factor alpha]] (TNF-α), [[interferon gamma]] (IFNγ), and [[granulocyte-macrophage colony stimulating factor|granulocyte-macrophage colony stimulating factor (GM-CSF)]] and play an important role in mediating the [[innate immune response]]. Inflammatory cytokines are predominantly produced by and involved in the upregulation of inflammatory reactions.

Excessive chronic production of inflammatory cytokines contribute to [[inflammatory disease]]s, that have been linked to different diseases, such as [[atherosclerosis]] and [[cancer]]. Dysregulation has also been linked to [[Mood disorder|depression]] and other neurological diseases. A balance between proinflammatory and anti-inflammatory cytokines is necessary to maintain health. [[Aging]] and [[exercise]] also play a role in the amount of inflammation from the release of proinflammatory cytokines.

Therapies to treat inflammatory diseases include [[monoclonal antibody therapy|monoclonal antibodies]] that either neutralize inflammatory cytokines or their [[cytokine receptor|receptors]].

==Definition==
An inflammatory cytokine is a type of [[cytokine]] (a signaling molecule) that is secreted from immune cells and certain other cell types that promotes [[inflammation]]. Inflammatory cytokines are predominantly produced by [[T helper cell]]s ('''Th''') and [[macrophage]]s and involved in the [[upregulation]] of inflammatory reactions.<ref name="Zhang 27–37">{{cite journal | vauthors = Zhang JM, An J | title = Cytokines, inflammation, and pain | journal = International Anesthesiology Clinics | volume = 45 | issue = 2 | pages = 27–37 | pmid = 17426506 | doi = 10.1097/aia.0b013e318034194e | pmc=2785020 | year=2007}}</ref> Therapies to treat inflammatory diseases include [[monoclonal antibody therapy|monoclonal antibodies]] that either neutralize inflammatory cytokines or their [[cytokine receptor|receptors]].<ref name="pmc4707170">{{cite journal | vauthors = Scarpioni R, Ricardi M, Albertazzi V | title = Secondary amyloidosis in autoinflammatory diseases and the role of inflammation in renal damage | journal = World Journal of Nephrology | volume = 5 | issue = 1 | pages = 66–75 | date = Jan 2016 | pmid = 26788465 | pmc = 4707170 | doi = 10.5527/wjn.v5.i1.66 | doi-access = free }}</ref>

Inflammatory cytokines include [[interleukin-1]] (IL-1), [[interleukin 12|IL-12]], and [[interleukin 18|IL-18]], [[tumor necrosis factor|tumor necrosis factor alpha]] (TNF-α), [[interferon gamma]] (IFNγ), and [[granulocyte-macrophage colony stimulating factor|granulocyte-macrophage colony stimulating factor (GM-CSF)]].<ref name="pmid11502077">{{cite journal | vauthors = Cavaillon JM | title = Pro- versus anti-inflammatory cytokines: myth or reality | journal = Cellular and Molecular Biology (Noisy-le-Grand, France) | volume = 47 | issue = 4 | pages = 695–702 | year = 2001 | pmid = 11502077 }}</ref>

== Function ==
Inflammatory cytokines play a role in initiating the inflammatory response and to regulate the host defence against pathogens mediating the [[innate immune response]].<ref>Chen L, Deng H, Cui H, et al. Inflammatory responses and inflammation-associated diseases in organs. Oncotarget. 2017;9(6):7204–7218. Published 2017 Dec 14. {{doi|10.18632/oncotarget.23208}}</ref> Some inflammatory cytokines have additional roles such as acting as [[Growth factor|growth factors]].<ref>{{cite book | last1 = Fitzgerald | first1 = Katherine A. | last2 = O'Neill | first2 = Luke A.J. | last3 = Gearing | first3 = Andy J.H. | last4 = Callard | first4 = Robin E. | name-list-style = vanc | title = The Cytokine Factsbook | date = 2001 | publisher = Academic Press | location = San Diego | isbn = 978-0-12-155142-1 | page = 2 | edition = 2nd }}</ref>
Pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α also trigger pathological pain.<ref name="Zhang 27–37"/> While IL-1β is released by monocytes and macrophages, it is also present in nociceptive DRG neurons. IL-6 plays a role in neuronal reaction to an injury. TNF-α is a well known proinflammatory cytokine present in neurons and the [[Neuroglia|glia]]. TNF-α is often involved in different signaling pathways to regulate [[apoptosis]] in the cells.{{citation needed|date=February 2017}}
Excessive chronic production of inflammatory cytokines contribute to [[inflammatory disease]]s.<ref name="pmc4707170"/> that have been linked to different diseases, such as [[atherosclerosis]] and [[cancer]]. Dysregulation of proinflammatory cytokines have also been linked to [[Mood disorder|depression]] and other neurological diseases. A balance between proinflammatory and anti-inflammatory cytokines is necessary to maintain health. Aging and exercise also play a role in the amount of inflammation from the release of proinflammatory cytokines.<ref name="ReferenceA">{{cite journal | vauthors = Sallam N, Laher I | title = Exercise Modulates Oxidative Stress and Inflammation in Aging and Cardiovascular Diseases | journal = Oxidative Medicine and Cellular Longevity | volume = 2016 | pages = 7239639 | date = 2015-12-28 | pmid = 26823952 | pmc = 4707375 | doi = 10.1155/2016/7239639 | doi-access = free }}</ref>

== Negative impacts ==

Due to its proinflammatory action, a proinflammatory cytokine tends to make the disease itself or the symptoms correlated to a disease worse by causing [[fever]], [[inflammation]], tissue destruction, and in some cases, even [[Shock (circulatory)|shock]] and [[death]].<ref name="pmid10936147">{{cite journal | vauthors = Dinarello CA | title = Proinflammatory cytokines | journal = Chest | volume = 118 | issue = 2 | pages = 503–8 | date = August 2000 | pmid = 10936147 | doi =10.1378/chest.118.2.503 }}</ref> Excessive amounts of proinflammatory cytokines have been shown to cause detrimental effects<ref name="pmc4707170"/>

=== In the kidney ===

A proinflammatory cytokine affects functions of transporters and [[Ion channel|ion channels]] from the [[nephron]]. As a result, there is a change in the activity of the [[Potassium|potassium ion]] (K+) channels that changes the transepithelial transport of solutes and water in the kidney.<ref>{{cite journal | vauthors = Nakamura K, Hayashi H, Kubokawa M | title = Proinflammatory Cytokines and Potassium Channels in the Kidney | language = en | journal = Mediators of Inflammation | volume = 2015 | pages = 362768 | date = 2015-10-05 | pmid = 26508816 | pmc = 4609835 | doi = 10.1155/2015/362768 | doi-access = free }}</ref> The kidney [[proximal tubule]] cells produce proinflammatory cytokines in response to [[lipopolysaccharide]]. Proinflammatory cytokines affect the renal K+ channels. IFNγ causes delayed suppression and acute stimulation of the 40 pS K+ channel. Also, [[Transforming growth factor beta family|transforming growth factor beta 1]] (TGF-β1) activates the calcium-activated potassium channel ([[Calcium-activated potassium channel|KCa3.1]]) which could be involved the detrimental effects of renal [[fibrosis]].{{citation needed|date=February 2017}}

=== Graft-vs-host disease ===

[[Graft-versus-host disease]] (GvHD) targets [[Janus kinase 1|JAK 1]] and [[Janus kinase 2|2]], the human [[tyrosine kinase]] protein required for signaling in multiple cytokines. When these [[Kinase|kinases]] are activated, signal proteins of the signal transducer and activator of transcription [[STAT protein|(STAT)]] protein family – which include transcription factors for target genes that serve proinflammatory roles – are [[Phosphorylation|phosphorylated]].<ref>{{cite journal | vauthors = Teshima T, Reddy P, Zeiser R | title = Acute Graft-versus-Host Disease: Novel Biological Insights | journal = Biology of Blood and Marrow Transplantation | volume = 22 | issue = 1 | pages = 11–6 | date = Jan 2016 | pmid = 26453971 | doi = 10.1016/j.bbmt.2015.10.001 | doi-access = free }}</ref> The severity of GvHD is highly variable and is influenced by the amount of native cells present in the environment along with other regulatory [[T cell|T cells]], [[T helper cell|TH1]], [[T helper cell|TH2]], or [[T helper cell|TH17]] phenotypes.<ref>{{cite journal | vauthors = Henden AS, Hill GR | title = Cytokines in Graft-versus-Host Disease | language = en | journal = Journal of Immunology | volume = 194 | issue = 10 | pages = 4604–12 | date = May 2015 | pmid = 25934923 | doi = 10.4049/jimmunol.1500117 | doi-access = free }}</ref> Both CD4+ and CD8 IL-17 producing T cells have been shown to cause aTH1, causing tissue inflammation and resulting in severe GVHD.<ref>{{cite journal | vauthors = van der Waart AB, van der Velden WJ, Blijlevens NM, Dolstra H | title = Targeting the IL17 pathway for the prevention of graft-versus-host disease | journal = Biology of Blood and Marrow Transplantation | volume = 20 | issue = 6 | pages = 752–9 | date = Jun 2014 | pmid = 24565991 | doi = 10.1016/j.bbmt.2014.02.007 | doi-access = free }}</ref>

=== In cystic fibrosis ===

A proinflammatory cytokine causes hyperinflammation, the leading cause of lung tissue destruction in [[cystic fibrosis]].<ref>{{cite journal | vauthors = Bruscia EM, Bonfield TL | title = Innate and Adaptive Immunity in Cystic Fibrosis | journal = Clinics in Chest Medicine | volume = 37 | issue = 1 | pages = 17–29 | date = Mar 2016 | pmid = 26857765 | doi = 10.1016/j.ccm.2015.11.010 }}</ref> With such a strong inflammatory response and an elevated number of immune cells, lungs of cystic fibrosis patients cannot clear the bacteria and become more susceptible to infections. A high prevalence (40-70%) of patients with cystic fibrosis show signs of [[asthma]], possibly due to the primary deficiency in the [[cystic fibrosis transmembrane conductance regulator]] (CFTR).<ref>{{cite journal | vauthors = McCuaig S, Martin JG | title = How the airway smooth muscle in cystic fibrosis reacts in proinflammatory conditions: implications for airway hyper-responsiveness and asthma in cystic fibrosis | journal = The Lancet Respiratory Medicine | volume = 1 | issue = 2 | pages = 137–47 | date = Apr 2013 | pmid = 24429094 | doi = 10.1016/s2213-2600(12)70058-9 }}</ref> CFTR-deficient T-helper cells create an inflammatory environment that has high concentrations of TNF-α, [[interleukin 8|IL-8]], and IL-13, which contributes to increased contractility of airway smooth muscle.{{citation needed|date=February 2017}}

=== In cardiovascular disease ===

[[Atherosclerosis]] induces a dysfunctional endothelium, which recruits immune cells that form lesions. Proinflammatory mediators cause inflammation after [[Ligand|ligands]] in the heart vasculature activate immune cells.<ref>{{cite journal | vauthors = Slocum C, Kramer C, Genco CA | title = Immune dysregulation mediated by the oral microbiome: potential link to chronic inflammation and atherosclerosis | language = en | journal = Journal of Internal Medicine | date = Jan 2016 | pmid = 26791914 | doi = 10.1111/joim.12476 | volume=280 | issue = 1 | pages=114–28| doi-access = free }}</ref> Recent studies have shown the ability of exercise to control oxidative stress and inflammation in cardiovascular disease.{{citation needed|date=February 2017}}

=== In adipose tissue metabolism and obesity ===
A proinflammatory cytokine may be present in [[Adipose tissue|adipose tissues]]. [[Adipocyte|Adipocytes]] generate TNF-α and other [[Interleukin|interleukins]]. Cytokines derived from [[adipose tissue]] serve as remote regulators such as [[Hormone|hormones]]. Studies have shown that TNF-α and IL-6 concentrations are elevated in [[obesity]].<ref>{{cite journal | vauthors = Coppack SW | title = Pro-inflammatory cytokines and adipose tissue | journal = The Proceedings of the Nutrition Society | volume = 60 | issue = 3 | pages = 349–56 | date = August 2001 | pmid = 11681809 | doi = 10.1079/PNS2001110 | doi-access = free }}</ref><ref name="pmid30591653">{{cite journal | vauthors=Kern L, Mittenbühler MJ, Vesting AJ, Wunderlich FT | title=Obesity-Induced TNFα and IL-6 Signaling: The Missing Link between Obesity and Inflammation-Driven Liver and Colorectal Cancers | journal=[[cancers]] | volume=11 | issue=1 | pages=24 | year=2018 | doi = 10.3390/cancers11010024 | pmc=6356226 | pmid=30591653 | doi-access=free }}</ref><ref name="pmid30165404">{{cite journal | vauthors=Virdis A, Colucci R, Bernardini N, Masi S | title=Microvascular Endothelial Dysfunction in Human Obesity: Role of TNF-α | journal=[[The Journal of Clinical Endocrinology and Metabolism]] | volume=104 | issue=2 | pages=341–348 | year=2019 | doi = 10.1210/jc.2018-00512 | pmid=30165404 | doi-access=free }}</ref> Obesity leaves an excess of nutrients for the body, thereby causing [[adipocyte]]s to release more proinflammatory cytokines. Classically activated macrophages in the visceral fat accumulate in the fat tissues and continuously release proinflammatory cytokines, causing chronic inflammation in obese individuals.{{citation needed|date=February 2017}}

=== In osteoarthritis ===
TNF-α, IL-1 and IL-6 have been found to play a pivotal role in [[cartilage]] matrix degradation and [[bone resorption]] in [[osteoarthritis]].<ref>{{cite journal |last1=Wang |first1=Tiantian |last2=He |first2=Chengqi |title=Pro-inflammatory cytokines: The link between obesity and osteoarthritis |journal=Cytokine & Growth Factor Reviews |date=December 2018 |volume=44 |pages=38–50 |doi=10.1016/j.cytogfr.2018.10.002 |pmid=30340925 |s2cid=53009998 }}</ref> Animal studies indicate that inflammatory cytokines may stimulate [[Chondrocyte|chondrocytes]] to release cartilage-degrading [[protease]] in osteoarthritis. This finding does not, however, necessarily translate to ''[[Homo sapiens]]'', as osteoarthritis in humans is considered to be more complex than any animal model.<ref>{{cite journal |last1=Goldring |first1=Mary B. |title=The Role of Cytokines as Inflammatory Mediators in Osteoarthritis: Lessons from Animal Models |journal=Connective Tissue Research |date=January 1999 |volume=40 |issue=1 |pages=1–11 |doi=10.3109/03008209909005273 |pmid=10770646 }}</ref>

===Fatigue===
Cytokines have key roles in inflammation, which is seen as a causal mechanism in [[fatigue]].<ref>{{cite journal | doi=10.3389/fimmu.2017.00021 | doi-access=free | title=Role of Inflammation in Human Fatigue: Relevance of Multidimensional Assessments and Potential Neuronal Mechanisms | year=2017 | last1=Karshikoff | first1=Bianka | last2=Sundelin | first2=Tina | last3=Lasselin | first3=Julie | journal=Frontiers in Immunology | volume=8 | page=21 | pmid=28163706 | pmc=5247454 }}</ref>

== Clinical implications ==
Reducing the biological activity of proinflammatory cytokine can reduce the brunt of attack from diseases.<ref name="pmid10936147" />

Blocking IL-1 or TNF-α has been highly successful in helping patients with rheumatoid arthritis, [[inflammatory bowel disease]],<ref name="pmid21530742">{{cite journal |last1=Strober |first1=Warren |last2=Fuss |first2=Ivan J. |title=Proinflammatory Cytokines in the Pathogenesis of Inflammatory Bowel Diseases |journal=Gastroenterology |date=May 2011 |volume=140 |issue=6 |pages=1756–1767.e1 |doi=10.1053/j.gastro.2011.02.016 |pmid=21530742 |pmc=3773507 }}</ref> or graft-vs-host disease (GvHD).<ref name="pmid10936147" /> However, the strategy has not yet been successful in humans with sepsis.<ref name="pmid10936147" /> Therapeutic effects of acupuncture may be related to the body's ability to suppress a range of proinflammatory cytokines such as [[tumor necrosis factor alpha|tumor necrosis factor alpha (TNF-α)]], [[IL1B|IL-1B]], [[interleukin 6|IL-6]], and [[interleukin 10|IL-10]].<ref>{{cite journal |last1=Wang |first1=Xiao-Min |last2=Walitt |first2=Brian |last3=Saligan |first3=Leorey |last4=Tiwari |first4=Agnes FY |last5=Cheung |first5=Chi Wai |last6=Zhang |first6=Zhang-Jin |title=Chemobrain: A critical review and causal hypothesis of link between cytokines and epigenetic reprogramming associated with chemotherapy |journal=Cytokine |date=March 2015 |volume=72 |issue=1 |pages=86–96 |doi=10.1016/j.cyto.2014.12.006 |pmid=25573802 |pmc=4750385 }}</ref>

[[Estrogen]] has been shown to promote healing by decreasing the production of various proinflammatory cytokines like IL-6,<ref>{{cite journal |last1=Canellada |first1=Andrea |last2=Alvarez |first2=Irene |last3=Berod |first3=Luciana |last4=Gentile |first4=Teresa |title=Estrogen and progesterone regulate the IL-6 signal transduction pathway in antibody secreting cells |journal=The Journal of Steroid Biochemistry and Molecular Biology |date=September 2008 |volume=111 |issue=3–5 |pages=255–261 |doi=10.1016/j.jsbmb.2008.06.009 |pmid=18619543 |s2cid=24957064 }}</ref> TNF-α,<ref>{{cite journal |last1=Fortini |first1=Francesca |last2=Vieceli Dalla Sega |first2=Francesco |last3=Caliceti |first3=Cristiana |last4=Lambertini |first4=Elisabetta |last5=Pannuti |first5=Antonio |last6=Peiffer |first6=Daniel S. |last7=Balla |first7=Cristina |last8=Rizzo |first8=Paola |title=Estrogen-mediated protection against coronary heart disease: The role of the Notch pathway |journal=The Journal of Steroid Biochemistry and Molecular Biology |date=May 2019 |volume=189 |pages=87–100 |doi=10.1016/j.jsbmb.2019.02.008 |pmid=30817989 |hdl=11392/2405957 |s2cid=72334147 |hdl-access=free }}</ref> and macrophage migration inhibitory factor ([[Macrophage migration inhibitory factor|MIF]]). Increased MIF levels are often found at the site of chronic non-healing ulcers, with those levels dropping significantly with successful healing. A 2005 review of current experimental data shows that "estrogen regulates healing almost exclusively via MIF down-regulation and identifies novel MIF-regulated gene targets and clusters associated with aberrant healing." By down-regulating MIF, estrogen can promote healing, as correlated by clinical studies on aging skin and skin wounds. Unfortunately, estrogen-therapy has known [[Carcinogen|carcinogenic]] effects<ref>{{Cite web|url=https://www.cancer.org/cancer/breast-cancer/treatment/hormone-therapy-for-breast-cancer.html|title=Hormone Therapy for Breast Cancer {{!}} American Cancer Society|website=www.cancer.org|language=en|access-date=2019-02-27}}</ref> as mentioned by the American Cancer Society (increased incidences of breast cancer in women who undergo [[Hormone replacement therapy|HRT]]). However, scientists could make important discoveries in the future by studying "downstream effects on genes/factors that mediate the effects of estrogen on healing."<ref>{{Cite web|url=https://www.woundsresearch.com/article/4908|title=Hormonal Influences on Wound Healing: A Review of Current Experimental Data|website=Wounds Research|language=en|access-date=2019-02-27}}</ref>

Histone deacetylate inhibitors ([[Histone deacetylase inhibitor|HDACi]]) can suppress proinflammatory cytokine production and reduce GvHD.{{citation needed|date=February 2017}}

Some research also suggest an immunoregulatory effect of vitamin D, which has been shown to reduce the secretion of specific inflammatory cytokines.<ref>{{cite journal |last1=Sharifi |first1=Amrollah |last2=Vahedi |first2=Homayoon |last3=Nedjat |first3=Saharnaz |last4=Rafiei |first4=Hossein |last5=Hosseinzadeh-Attar |first5=Mohammad Javad |title=Effect of single-dose injection of vitamin D on immune cytokines in ulcerative colitis patients: a randomized placebo-controlled trial |journal=APMIS |date=October 2019 |volume=127 |issue=10 |pages=681–687 |doi=10.1111/apm.12982 |pmid=31274211 |s2cid=195806132 }}</ref><ref>{{cite journal |last1=Ohaegbulam |first1=Kim C. |last2=Swalih |first2=Mohamed |last3=Patel |first3=Pranavkumar |last4=Smith |first4=Miriam A. |last5=Perrin |first5=Richard |title=Vitamin D Supplementation in COVID-19 Patients: A Clinical Case Series |journal=American Journal of Therapeutics |date=September 2020 |volume=27 |issue=5 |pages=e485–e490 |doi=10.1097/MJT.0000000000001222 |pmid=32804682 |pmc=7473790 }}</ref>

== References ==
{{Reflist|33em}}

{{Cytokines}}
{{Cytokine receptor modulators}}

[[Category:Cytokines]]

Inflammatory cytokine - Revision history

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