View source for Interleukin 19

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}

'''Interleukin 19''' (IL-19) is an immunosuppressive [[protein]] that belongs to the [[Interleukin 10|IL-10]] cytokine subfamily.

Human IL-19 is encoded by the IL-19 [[gene]] which codes for 9 exons and is located on [[chromosome]] 1.<ref name=":0">{{Cite web |title=IL19 interleukin 19 [Homo sapiens (human)] - Gene - NCBI |url=https://www.ncbi.nlm.nih.gov/gene/29949 |access-date=2022-03-01 |website=www.ncbi.nlm.nih.gov}}</ref> The IL-19 protein is composed of 159 amino acids and has a quaternary structure with alpha helix motifs and loops. IL-19 is preferentially expressed in monocytes, macrophages, and T and B lymphocytes,<ref name=":0" /> but interacts with immune cells ([[macrophage]]s, [[T cell]]s, [[B cell]]s) and non-immune cells ([[Endothelium|endothelial cells]] and brain resident [[glia]]l cells, etc).<ref name=":2">{{cite journal | vauthors = Leigh T, Scalia RG, Autieri MV | title = Resolution of inflammation in immune and nonimmune cells by interleukin-19 | journal = American Journal of Physiology. Cell Physiology | volume = 319 | issue = 3 | pages = C457–C464 | date = September 2020 | pmid = 32667867 | pmc = 7509264 | doi = 10.1152/ajpcell.00247.2020 }}</ref>

IL-19 initiates [[JAK-STAT signaling pathway|JAK-STAT]] signaling which activates genes and creates mRNA sequences ([[Transcription (biology)|transcription]]) that are translated into proteins ([[Translation (biology)|translation]]) which have downstream effector functions. IL-19 signaling uses [[Interleukin-20 receptor|IL-20]] dimer receptor complexes that bind the IL-19 ligand, [[Janus kinase]]s (JAKs), and the signal transducer and activator of transcription 3 ([[STAT3]]) to initiate the molecular signaling cascade shown on the diagram on the right.

== Function ==

IL-19 is associated with broad functions across inflammation, cell development, viral responses, and lipid metabolism.<ref name=":0" /> As an immunosuppressive cytokine, IL-19 promotes the [[T helper cell|Th2 (regulatory) T-cell response]] which supports an anti-inflammatory lymphocyte phenotype, dampens the Th1 T-cell response and inflammatory cytokine secretion ([[Interferon gamma|IFNγ]]), increases [[IL-10 family|IL-10]] (anti-inflammatory) expression in peripheral blood mononuclear cells ([[Peripheral blood mononuclear cell|PBMC]]), and inhibits the production of [[immunoglobulin G]] (IgG) from [[B cell]]s.<ref name=":2" /><ref>{{cite journal | vauthors = Gallagher G | title = Interleukin-19: multiple roles in immune regulation and disease | journal = Cytokine & Growth Factor Reviews | volume = 21 | issue = 5 | pages = 345–352 | date = October 2010 | pmid = 20889366 | doi = 10.1016/j.cytogfr.2010.08.005 | series = IL-10 Family of Cytokines }}</ref>

=== Cell adhesion molecule regulation ===
IL-19 suppresses the expression of RNA-binding protein HuR.<ref name=":5">{{cite journal | vauthors = Scott DW, Patel RP | title = Targeting endothelial adhesion molecule mRNA to control inflammation: novel insights into potential anti-inflammatory effects of IL-19. Focus on "Interleukin-19 decreases leukocyte-endothelial cell interactions by reduction in endothelial cell adhesion molecule mRNA stability" | journal = American Journal of Physiology. Cell Physiology | volume = 305 | issue = 3 | pages = C253–C254 | date = August 2013 | pmid = 23657567 | doi = 10.1152/ajpcell.00120.2013 | s2cid = 21613016 }}</ref> This protein is responsible for stabilizing mRNA that codes for [[cell adhesion molecule]]s (CAMs) which are secreted by activated macrophages and facilitate [[neutrophil]] extravasation into peripheral or [[Heart|cardiac]] tissue.<ref name=":5" /> The downregulation of this factor affects the translation adhesion molecules which are expressed in the endothelial cells lined up in blood vessels.<ref name=":5" /> A reduced number of neutrophils entering cardiac tissue serves as a protective mechanism that limits the vascular tissue  damage that ensues from inflammatory processes.<ref name=":5" />

=== Chronic inflammatory disease ===
IL-19 has been reported to enhance chronic inflammatory diseases. IL-19 is produced by and regulates cells of the monocyte lineage, such as alveolar [[macrophage]]s and lung [[dendritic cell]]s.<ref name=":4">{{cite journal | vauthors = Hoffman C, Park SH, Daley E, Emson C, Louten J, Sisco M, de Waal Malefyt R, Grunig G | display-authors = 6 | title = Interleukin-19: a constituent of the regulome that controls antigen presenting cells in the lungs and airway responses to microbial products | journal = PLOS ONE | volume = 6 | issue = 11 | pages = e27629 | date = 2011-11-15 | pmid = 22110701 | pmc = 3217014 | doi = 10.1371/journal.pone.0027629 | bibcode = 2011PLoSO...627629H | doi-access = free }}</ref> Several studies have used IL-19-deficient (IL-19-/-) mice and tested them at baseline (naïve) and following immune challenge with microbial products or recombinant cytokines.<ref name=":4" /> Naïve IL-19-/- mice show a decreased percentage of monocyte-derived cells and express significantly less MHC class II in response to stimulation with exogenous antigens such as [[lipopolysaccharide]] (LPS).<ref name=":4" /> IL-19-/- mice also show dysregulated neurogenic-locus-notch-homolog-protein-2 ([[Notch 2|Notch2]]) expression which plays a role in cell differentiation.<ref name=":4" /> Since [[MHC class II]] mediates peptide presentation to T cells and Notch 2 determines cell fate decision, endogenous IL-19 appears to regulate both processes.<ref name=":4" />[[File:A demonstration of IL-19 binds to IL20 Receptor on the surface of immune cells to regulate cytokines expression.png|thumb|A demonstration of IL-19 binding to the IL20 Receptor on the surface of immune cells to regulate cytokine expression]]

=== Immune cell polarization ===
The induction of the anti-inflammatory cytokines [[Interleukin 10|IL-10]] and [[Interleukin 4|IL-4]] and the downregulation of pro-inflammatory cytokines such as [[Interferon gamma|IFN-γ]] shifts the phenotype of a [[T helper cell]] away from T-helper 1 (Th1) phenotype and towards the T-helper 2 (Th2) phenotype.<ref>{{cite journal | vauthors = Autieri MV | title = IL-19 and Other IL-20 Family Member Cytokines in Vascular Inflammatory Diseases | journal = Frontiers in Immunology | volume = 9 | pages = 700 | date = 2018 | pmid = 29681905 | doi = 10.3389/fimmu.2018.00700 | pmc = 5897441 | doi-access = free }}</ref> This process of immune cell polarization occurs when immune cells adopt distinct programs and perform specialized functions in response to specific signals.<ref>{{cite journal | vauthors = Ma Q | title = Polarization of Immune Cells in the Pathologic Response to Inhaled Particulates | journal = Frontiers in Immunology | volume = 11 | pages = 1060 | date = 2020 | pmid = 32625201 | doi = 10.3389/fimmu.2020.01060 | pmc = 7311785 | doi-access = free }}</ref> During vascular infection (bacterial, fungal or viral infection develops within an artery or a vein), the Th1 phenotype predominates in the T cell population, and interferon-gamma ([[Interferon gamma|IFN-γ]]), tumor necrosis factor-alpha ([[Tumor necrosis factor|TNF-α]]), and other pro-inflammatory cytokines are secreted at high levels.<ref name=":6">{{cite journal | vauthors = Lintermans LL, Stegeman CA, Heeringa P, Abdulahad WH | title = T cells in vascular inflammatory diseases | journal = Frontiers in Immunology | volume = 5 | pages = 504 | date = 2014 | pmid = 25352848 | doi = 10.3389/fimmu.2014.00504 | pmc = 4196542 | doi-access = free }}</ref> If cytokine secretion is left unrestricted, there may be potential consequences including vessel or tissue damage. In contrast, cells with the Th2 phenotype secrete IL-4 and IL-10 and downregulate IFN-γ which collectively dampen the inflammatory response.<ref name=":6" /> Analogously to [[lymphocyte]]s, [[macrophage]]s receiving the IL-19 signal are polarized from the pro-inflammatory phenotype ([[M1 macrophage|M1]]) to the anti-inflammatory phenotype ([[M2 macrophage|M2]]).<ref name=":6" />

=== Neutrophil development ===
[[Osteocyte]]s are the most abundant cells in the bone and they are responsible for bone health.<ref>{{cite journal | vauthors = Metzger CE, Narayanan SA | title = The Role of Osteocytes in Inflammatory Bone Loss | journal = Frontiers in Endocrinology | volume = 10 | pages = 285 | date = 2019 | pmid = 31139147 | doi = 10.3389/fendo.2019.00285 | pmc = 6527760 | doi-access = free }}</ref> Osteocytes are important regulators of hematopoiesis so they are important in aiding cellular development. Studies with mice have shown that the constitutive activation of mechanistic target of rapamycin complex (a [[protein complex]] that functions as a nutrient/energy /redox sensor and controls protein synthesis), or [[mTORC1]] in osteocytes shows a dramatic increase in IL-19 production and expands neutrophil precursor numbers.<ref name=":7">{{cite journal | vauthors = Xiao M, Zhang W, Liu W, Mao L, Yang J, Hu L, Zhang S, Zheng Y, Liu A, Song Q, Li Y, Xiao G, Zou Z, Bai X | display-authors = 6 | title = Osteocytes regulate neutrophil development through IL-19: a potent cytokine for neutropenia treatment | journal = Blood | volume = 137 | issue = 25 | pages = 3533–3547 | date = June 2021 | pmid = 33684929 | pmc = 8225922 | doi = 10.1182/blood.2020007731 }}</ref> IL-19 administration also stimulated neutrophil development but the depletion of endogenous IL-19 or its cognate receptor inhibited cell development, suggesting that IL-19 is an essential regulator of neutrophil development.<ref name=":7" />

=== Lipid metabolism ===
[[Non-alcoholic fatty liver disease|Nonalcoholic steatohepatitis]] (NASH) is a disease that has progressed from [[Non-alcoholic fatty liver disease|nonalcoholic fatty liver disease]] (NAFLD) and is characterized by inflammation and [[fibrosis]].<ref>{{cite journal | vauthors = Azuma YT, Fujita T, Izawa T, Hirota K, Nishiyama K, Ikegami A, Aoyama T, Ike M, Ushikai Y, Kuwamura M, Fujii H, Tsuneyama K | display-authors = 6 | title = IL-19 Contributes to the Development of Nonalcoholic Steatohepatitis by Altering Lipid Metabolism | journal = Cells | volume = 10 | issue = 12 | pages = 3513 | date = December 2021 | pmid = 34944021 | pmc = 8699936 | doi = 10.3390/cells10123513 | doi-access = free }}</ref> Findings showed that the effects of a high fat diet on liver injury, inflammation, and fibrosis were significantly worse in IL-19 gene-deficient mice than controls. This is congruous with a significantly higher secretion of IL-6, TNF-α, and TGF-β secretion (pro-inflammatory cytokines) in IL-19 gene-deficient mice. IL-19 administration decreased triglyceride and cholesterol levels in [[Hep G2|HepG2]] cells (isolated from a hepatocellular carcinoma patient) and the expression of fatty acid synthesis-related enzymes (reduced [[lipogenesis]]).<ref>{{Cite web |title=Hep G2 [HEPG2] {{!}} ATCC |url=https://www.atcc.org/products/hb-8065 |access-date=2022-03-01 |website=www.atcc.org}}</ref> IL-19 is therefore closely linked to the suppression of lipid metabolism.

=== Neuroprotection ===
The resident glial cells of the [[central nervous system]] participate in the initiation and regulation of neuroinflammation. Glial cells such as [[microglia]] and [[astrocyte]]s secrete proinflammatory cytokines in response to foreign antigens and immunosuppressive cytokines to resolve [[inflammation]] at the recovery phase of the immune response.<ref name=":1">{{cite journal | vauthors = Burmeister AR, Marriott I | title = The Interleukin-10 Family of Cytokines and Their Role in the CNS | journal = Frontiers in Cellular Neuroscience | volume = 12 | pages = 458 | date = 2018 | pmid = 30542269 | doi = 10.3389/fncel.2018.00458 | pmc = 6277801 | doi-access = free }}</ref> Within the brain, IL-19 is secreted by astrocytes in a delayed fashion.<ref name=":1" /> The IL-19 ligand interacts with cells expressing [[Interleukin-20 receptor|IL-20 receptors]] such as microglia and initiate a signaling cascade that regulates [[cytokine]] secretion.<ref name=":1" /> IL-19 signaling acts as secondary neuroprotective pathway that limits the inflammatory response and protect the brain from CNS insults.<ref name=":1" />

=== Autoimmunity ===
[[Interleukin 17|IL-17A]] is implicated in the immune response and in the pathogenesis of inflammatory autoimmune diseases such as [[psoriasis]].<ref>{{cite journal | vauthors = Xu X, Prens E, Florencia E, Leenen P, Boon L, Asmawidjaja P, Mus AM, Lubberts E | display-authors = 6 | title = Interleukin-17A Drives IL-19 and IL-24 Expression in Skin Stromal Cells Regulating Keratinocyte Proliferation | journal = Frontiers in Immunology | volume = 12 | pages = 719562 | date = 2021 | pmid = 34616394 | pmc = 8488340 | doi = 10.3389/fimmu.2021.719562 | doi-access = free }}</ref> IL-17A upregulates IL-19, IL-20, and IL-24 and this was shown by enhanced IL-17A expression using anti-IL-10 [[Neutralizing antibody|neutralizing antibodies]] (block IL-10 inhibitory effects and facilitate cytokine secretion). Findings showed upregulated IL-23/IL-17 pathway related cytokines, IL-19, and IL-24, pronounced inflammation, and [[keratinocyte]] proliferation.<ref>{{cite journal | vauthors = von Stebut E, Boehncke WH, Ghoreschi K, Gori T, Kaya Z, Thaci D, Schäffler A | title = IL-17A in Psoriasis and Beyond: Cardiovascular and Metabolic Implications | journal = Frontiers in Immunology | volume = 10 | pages = 3096 | date = 2020 | pmid = 32010143 | doi = 10.3389/fimmu.2019.03096 | pmc = 6974482 | doi-access = free }}</ref>

=== HIV ===
The most effective current treatment for HIV is [[combination antiretroviral therapy]] (cART) which stops the virus from making copies of itself using host cells and slows down the development of AIDS. Although cART therapy can help HIV-infected patients recover CD4+ T cells, there are several factors that affect T cell restoration and the maintenance of an undetectable viral load. One of these factors is [[Single-nucleotide polymorphism|single nucleotide polymorphisms]] (SNPs) in immune relevant cytokines (IL-15, IFNγ, IL-19).<ref name=":3">{{cite journal | vauthors = García M, Jiménez-Sousa MA, Blanco J, Restrepo C, Pacheco YM, Brochado-Kith Ó, López-Bernaldo JC, Gutiérrez F, Portilla J, Estrada V, Górgolas M, Cabello A, Resino S, Benito JM, Rallón N | display-authors = 6 | title = CD4 recovery is associated with genetic variation in IFNγ and IL19 genes | journal = Antiviral Research | volume = 170 | pages = 104577 | date = October 2019 | pmid = 31386862 | doi = 10.1016/j.antiviral.2019.104577 | s2cid = 199469343 }}</ref>

While many individuals respond to cART, there are individuals who are immunological non-responders (INR) which means that the density of T helper cells they have is below the 200 cells/μL threshold after two years on successful cART.<ref name=":3" /> Correlational studies have shown that polymorphisms in the IFNγ and IL-19 genes significantly impact the probability of failing to achieve an optimal immune recovery in HIV-patients starting cART.<ref name=":3" />[[File:The anti-inflammatory effect of IL-19 in vascular diseases.png|thumb|A demonstration of the protective effect of IL-19 in vascular disease by decreasing immune cell recruitment to inflamed tissue and reducing oxidative stress.]]

=== Other relevant functions ===
IL-19 upregulates the expression of [[Heme oxygenase|heme oxygenase-1]] (HO-1) and reduces [[reactive oxygen species]] in human vascular [[smooth muscle]] cells.<ref name="Autieri_2018">{{cite journal | vauthors = Autieri MV | title = IL-19 and Other IL-20 Family Member Cytokines in Vascular Inflammatory Diseases | language = English | journal = Frontiers in Immunology | volume = 9 | pages = 700 | date = 2018 | pmid = 29681905 | pmc = 5897441 | doi = 10.3389/fimmu.2018.00700 | doi-access = free }}</ref>

== IL-10 family ==
Interleukin-19 is a [[cytokine]] that belongs to the [[Interleukin 10|IL-10]] family of cytokines along with several other [[interleukin]]s including [[interleukin 10|IL-10]], [[interleukin 20|IL-20]], [[interleukin 22|IL-22]], [[interleukin 24|IL-24]], [[interleukin 26|IL-26]], and several [[virus]]-encoded cytokines.  It signals through the same cell surface receptor (IL-20R) that is used by IL-20 and IL-24.
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== References == 
{{Reflist|30em}}

== External links ==
* {{PDBe-KB2|Q9UHD0|Interleukin-19}}

{{Interleukins}}
{{Interleukin receptor modulators}}
{{NLM content}}

[[Category:Interleukins]]