Interleukin 19
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| Location (UCSC) | Chr 1: 206.77 – 206.84 Mb | Chr 1: 130.86 – 130.87 Mb | |||||||
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Interleukin 19 (IL-19) is an immunosuppressive protein that belongs to the 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.[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 resident glial cells, etc).[6]
IL-19 initiates JAK-STAT signaling which activates genes and creates mRNA sequences (transcription) that are translated into proteins (translation) which have downstream effector functions. IL-19 signaling uses IL-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.
Function
IL-19 is associated with broad functions across inflammation, cell development, viral responses, and lipid metabolism.[5] As an immunosuppressive cytokine, IL-19 promotes the Th2 (regulatory) T-cell response which supports an anti-inflammatory lymphocyte phenotype, dampens the Th1 T-cell response and inflammatory cytokine secretion (IFNγ), increases IL-10 (anti-inflammatory) expression in peripheral blood mononuclear cells (PBMC), and inhibits the production of immunoglobulin G (IgG) from B cells.[6][7]
Cell adhesion molecule regulation
IL-19 suppresses the expression of RNA-binding protein HuR.[8] This protein is responsible for stabilizing mRNA that codes for cell adhesion molecules (CAMs) which are secreted by activated macrophages and facilitate neutrophil extravasation into peripheral or cardiac 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 an protective mechanism that limits the vascular tissue damage that ensues from inflammatory processes.[8]
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 macrophages and lung dendritic 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 as lipopolysaccharide (LPS).[9] IL-19-/- mice also show dysregulated neurogenic-locus-notch-homolog-protein-2 (Notch2) expression which plays a role in cell differentiation.[9] 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.[9]
Immune cell polarization
The induction of the anti-inflammatory cytokines
Neutrophil development
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 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.[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]
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 astrocytes secrete proinflammatory cytokines in response to foreign antigens and immunosuppressive cytokines to resolve inflammation 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 expressing IL-20 receptors such as microglia and initiate a signaling cascade that regulates cytokine secretion.[17] IL-19 signaling acts as secondary neuroprotective pathway that limits the inflammatory response and protect the brain from CNS insults.[17]
Autoimmunity
IL-17A is implicated in the immune response and in the pathogenesis of inflammatory autoimmune diseases such as psoriasis.[18] IL-17A upregulates IL-19, IL-20, and IL-24 and this was shown by enhanced IL-17A expression using anti-IL-10 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.[19]
HIV
The most effective current treatment for HIV is
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]
Other relevant functions
IL-19 upregulates the expression of heme oxygenase-1 (HO-1) and reduces reactive oxygen species in human vascular smooth muscle cells.[21]
IL-10 family
Interleukin-19 is a cytokine that belongs to the IL-10 family of cytokines along with several other interleukins including IL-10, IL-20, IL-22, IL-24, 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.
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000142224 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000016524 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b c "IL19 interleukin 19 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-03-01.
- ^ PMID 32667867.
- PMID 20889366.
- ^ S2CID 21613016.
- ^ PMID 22110701.
- PMID 29681905.
- PMID 32625201.
- ^ PMID 25352848.
- PMID 31139147.
- ^ PMID 33684929.
- PMID 34944021.
- ^ "Hep G2 [HEPG2] | ATCC". www.atcc.org. Retrieved 2022-03-01.
- ^ PMID 30542269.
- PMID 34616394.
- PMID 32010143.
- ^ S2CID 199469343.
- PMID 29681905.
External links
- Overview of all the structural information available in the PDB for UniProt: Q9UHD0 (Interleukin-19) at the PDBe-KB.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.