Interleukin 19 (IL-19) is an immunosuppressiveprotein that belongs to theIL-10 cytokine subfamily.
Human IL-19 is encoded by the IL-19gene which codes for 9 exons and is located onchromosome 1.[5] 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,[5] but interacts with immune cells (macrophages,T cells,B cells) and non-immune cells (endothelial cells and brain residentglial cells, etc).[6]
IL-19 initiatesJAK-STAT signaling which activates genes and creates mRNA sequences (transcription) that are translated into proteins (translation) which have downstream effector functions. IL-19 signaling usesIL-20 dimer receptor complexes that bind the IL-19 ligand,Janus kinases (JAKs), and the signal transducer and activator of transcription 3 (STAT3) to initiate the molecular signaling cascade shown on the diagram on the right.
IL-19 is associated with broad functions across inflammation, cell development, viral responses, and lipid metabolism.[5] As an immunosuppressive cytokine, IL-19 promotes theTh2 (regulatory) T-cell response which supports an anti-inflammatory lymphocyte phenotype, dampens the Th1 T-cell response and inflammatory cytokine secretion (IFNγ), increasesIL-10 (anti-inflammatory) expression in peripheral blood mononuclear cells (PBMC), and inhibits the production ofimmunoglobulin G (IgG) fromB cells.[6][7]
IL-19 suppresses the expression of RNA-binding protein HuR.[8] This protein is responsible for stabilizing mRNA that codes forcell adhesion molecules (CAMs) which are secreted by activated macrophages and facilitateneutrophil extravasation into peripheral orcardiac tissue.[8] The downregulation of this factor affects the translation adhesion molecules which are expressed in the endothelial cells lined up in blood vessels.[8] A reduced number of neutrophils entering cardiac tissue serves as a protective mechanism that limits the vascular tissue damage that ensues from inflammatory processes.[8]
IL-19 has been reported to enhance chronic inflammatory diseases. IL-19 is produced by and regulates cells of the monocyte lineage, such as alveolarmacrophages and lungdendritic cells.[9] 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.[9] 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 aslipopolysaccharide (LPS).[9] IL-19-/- mice also show dysregulated neurogenic-locus-notch-homolog-protein-2 (Notch2) expression which plays a role in cell differentiation.[9] SinceMHC class II mediates peptide presentation to T cells and Notch 2 determines cell fate decision, endogenous IL-19 appears to regulate both processes.[9]
The induction of the anti-inflammatory cytokinesIL-10 andIL-4 and the downregulation of pro-inflammatory cytokines such asIFN-γ shifts the phenotype of aT helper cell away from T-helper 1 (Th1) phenotype and towards the T-helper 2 (Th2) phenotype.[10] This process of immune cell polarization occurs when immune cells adopt distinct programs and perform specialized functions in response to specific signals.[11] 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 (IFN-γ), tumor necrosis factor-alpha (TNF-α), and other pro-inflammatory cytokines are secreted at high levels.[12] 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.[12] Analogously tolymphocytes,macrophages receiving the IL-19 signal are polarized from the pro-inflammatory phenotype (M1) to the anti-inflammatory phenotype (M2).[12]
Osteocytes are the most abundant cells in the bone and they are responsible for bone health.[13] Osteocytes are important regulators of hematopoiesis so they are important in aiding cellular development. Studies with mice have shown that theconstitutive activation of mechanistic target of rapamycin complex (aprotein complex that functions as a nutrient/energy /redox sensor and controls protein synthesis), ormTORC1 in osteocytes shows a dramatic increase in IL-19 production and expands neutrophil precursor numbers.[14] 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.[14]
Nonalcoholic steatohepatitis (NASH) is a disease that has progressed fromnonalcoholic fatty liver disease (NAFLD) and is characterized by inflammation andfibrosis.[15] 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 inHepG2 cells (isolated from a hepatocellular carcinoma patient) and the expression of fatty acid synthesis-related enzymes (reducedlipogenesis).[16] IL-19 is therefore closely linked to the suppression of lipid metabolism.
The resident glial cells of thecentral nervous system participate in the initiation and regulation of neuroinflammation. Glial cells such asmicroglia andastrocytes secrete proinflammatory cytokines in response to foreign antigens and immunosuppressive cytokines to resolveinflammation at the recovery phase of the immune response.[17] Within the brain, IL-19 is secreted by astrocytes in a delayed fashion.[17] The IL-19 ligand interacts with cells expressingIL-20 receptors such as microglia and initiate a signaling cascade that regulatescytokine secretion.[17] IL-19 signaling acts as secondary neuroprotective pathway that limits the inflammatory response and protect the brain from CNS insults.[17]
IL-17A is implicated in the immune response and in the pathogenesis of inflammatory autoimmune diseases such aspsoriasis.[18] IL-17A upregulates IL-19, IL-20, and IL-24 and this was shown by enhanced IL-17A expression using anti-IL-10neutralizing 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, andkeratinocyte proliferation.[19]
The most effective current treatment for HIV iscombination 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 issingle nucleotide polymorphisms (SNPs) in immune relevant cytokines (IL-15, IFNγ, IL-19).[20]
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.[20] 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.[20]
IL-19 upregulates the expression ofheme oxygenase-1 (HO-1) and reducesreactive oxygen species in human vascularsmooth muscle cells.[21]
Interleukin-19 is acytokine that belongs to theIL-10 family of cytokines along with several otherinterleukins includingIL-10,IL-20,IL-22,IL-24,IL-26, and severalvirus-encoded cytokines. It signals through the same cell surface receptor (IL-20R) that is used by IL-20 and IL-24.
This article incorporates text from theUnited States National Library of Medicine, which is in thepublic domain.
