User:Immcarle173/Interleukin 19
Interleukin 19 (IL-19) is a protein that belongs to the IL-10 cytokine subfamily. Human IL-19 is encoded by the IL-19 gene located on chromosome 1. [1]
Interleukin 19 (IL-19)
[edit]
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. [1] 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,[1] but interacts with immune cells (macrophages, T cells, B cells) and non-immune cells (endothelial cells and brain resident glial cells, etc).[2]
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.
IL-19 is associated with broad functions across inflammation, cell development, viral responses, and lipid metabolism.[1] 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.[2][3]
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IL-19 Functions
[edit]IL-19 and Cell Adhesion Molecule Regulation
[edit]IL-19 suppresses the expression of RNA-binding protein HuR.[4] 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.[4] The downregulation of this factor affects the translation adhesion molecules which are expressed in the endothelial cells lined up in blood vessels.[4] A reduced number of neutrophils entering cardiac tissue serves as an protective mechanism that limits the vascular tissue damage that ensues from inflammatory processes.[4]
IL-19 and Chronic Inflammatory Disease
[edit]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.[5] 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.[5] 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).[5] IL-19-/- mice also show dysregulated neurogenic-locus-notch-homolog-protein-2 (Notch2) expression which plays a role in cell differentiation.[5] 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.[5]
IL-19 and Immune Cell Polarization
[edit]The induction of the anti-inflammatory cytokines IL-10 and IL-4 and the downregulation of pro-inflammatory cytokines such as 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.[6] This process of immune cell polarization occurs when immune cells adopt distinct programs and perform specialized functions in response to specific signals.[7] 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.[8] If cytokine secretion is left unrestricted, there may be potential consequences including vessel or tissue damage. Contrastively, cells with the Th2 phenotype secrete IL-4 and IL-10 and downregulate IFN-γ which collectively dampen the inflammatory response.[8] Analogously to lymphocytes, macrophages receiving the IL-19 signal are polarized from the pro-inflammatory phenotype (M1) to the anti-inflammatory phenotype (M2).[8]
IL-19 and Neutrophil Development
[edit]Osteocytes are the most abundant cells in the bone and they are responsible for bone health[9]. 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.[10] 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.[10]
IL-19 and Lipid Metabolism
[edit]Nonalcoholic steatohepatitis (NASH) is a disease that has progressed from nonalcoholic fatty liver disease (NAFLD) and is characterized by inflammation and fibrosis.[11] 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 HepG2 cells (isolated from a hepatocellular carcinoma patient) and the expression of fatty acid synthesis-related enzymes (reduced lipogenesis).[12] IL-19 is therefore closely linked to the suppression of lipid metabolism.
IL-19 and Neuroprotection
[edit]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.[13] Within the brain, IL-19 is secreted by astrocytes in a delayed fashion.[13] The IL-19 ligand interacts with cells expressing IL-20 receptors such as microglia and initiate a signaling cascade that regulates cytokine secretion.[13] IL-19 signaling acts as secondary neuroprotective pathway that limits the inflammatory response and protect the brain from CNS insults. [13]
IL-19 and Autoimmunity
[edit]IL-17A is implicated in the immune response and in the pathogenesis of inflammatory autoimmune diseases such as psoriasis.[14] 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.[15]
IL-19 and HIV
[edit]The human immunodeficiency viruses (HIV) are two species of Lentivirus that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive. This condition targets and kills CD4+ T Helper cells which are responsible for cell-mediated immunity. 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 polymorphisms (SNPs) in immune relevant cytokines (IL-15, IFNγ, IL-19).[16]
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.[16] 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.[16]
References
[edit]- ^ a b c d "IL19 interleukin 19 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-03-01.
- ^ a b Leigh, Tani; Scalia, Rosario G.; Autieri, Michael V. (2020-09-01). "Resolution of inflammation in immune and nonimmune cells by interleukin-19". American Journal of Physiology-Cell Physiology. 319 (3): C457–C464. doi:10.1152/ajpcell.00247.2020. ISSN 0363-6143. PMC 7509264. PMID 32667867.
{{cite journal}}: CS1 maint: PMC format (link) - ^ Gallagher, Grant (2010-10-01). "Interleukin-19: Multiple roles in immune regulation and disease". Cytokine & Growth Factor Reviews. IL-10 Family of Cytokines. 21 (5): 345–352. doi:10.1016/j.cytogfr.2010.08.005. ISSN 1359-6101.
- ^ a b c d Scott, David W.; Patel, Rakesh P. (2013-08-01). "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"". American Journal of Physiology-Cell Physiology. 305 (3): C253–C254. doi:10.1152/ajpcell.00120.2013. ISSN 0363-6143.
- ^ a b c d e Hoffman, Carol; Park, Sung-Hyun; Daley, Eleen; Emson, Claire; Louten, Jennifer; Sisco, Maureen; Malefyt, Rene de Waal; Grunig, Gabriele (2011-11-15). "Interleukin-19: A Constituent of the Regulome That Controls Antigen Presenting Cells in the Lungs and Airway Responses to Microbial Products". PLOS ONE. 6 (11): e27629. doi:10.1371/journal.pone.0027629. ISSN 1932-6203. PMC 3217014. PMID 22110701.
{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link) - ^ Autieri, Michael V. (2018). "IL-19 and Other IL-20 Family Member Cytokines in Vascular Inflammatory Diseases". Frontiers in Immunology. 9. doi:10.3389/fimmu.2018.00700/full. ISSN 1664-3224.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Ma, Qiang (2020). "Polarization of Immune Cells in the Pathologic Response to Inhaled Particulates". Frontiers in Immunology. 11. doi:10.3389/fimmu.2020.01060/full#:~:text=polarization%20of%20immune%20cells%20is,in%20response%20to%20specific%20signals.. ISSN 1664-3224.
{{cite journal}}: Check|doi=value (help) - ^ a b c Lintermans, Lucas L.; Stegeman, Coen A.; Heeringa, Peter; Abdulahad, Wayel H. (2014). "T Cells in Vascular Inflammatory Diseases". Frontiers in Immunology. 5. doi:10.3389/fimmu.2014.00504/full. ISSN 1664-3224.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Metzger, Corinne E.; Narayanan, S. Anand (2019). "The Role of Osteocytes in Inflammatory Bone Loss". Frontiers in Endocrinology. 10. doi:10.3389/fendo.2019.00285/full. ISSN 1664-2392.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ a b Xiao, Min; Zhang, Wuju; Liu, Wen; Mao, Linlin; Yang, Jincheng; Hu, Le; Zhang, Sheng; Zheng, Yaling; Liu, Anling; Song, Qiancheng; Li, Yuhua (2021-06-24). "Osteocytes regulate neutrophil development through IL-19: a potent cytokine for neutropenia treatment". Blood. 137 (25): 3533–3547. doi:10.1182/blood.2020007731. ISSN 1528-0020. PMC 8225922. PMID 33684929.
- ^ Azuma, Yasu-Taka; Fujita, Takashi; Izawa, Takeshi; Hirota, Kana; Nishiyama, Kazuhiro; Ikegami, Airi; Aoyama, Tomoko; Ike, Mikihito; Ushikai, Yumi; Kuwamura, Mitsuru; Fujii, Hideki (2021-12-13). "IL-19 Contributes to the Development of Nonalcoholic Steatohepatitis by Altering Lipid Metabolism". Cells. 10 (12): 3513. doi:10.3390/cells10123513. ISSN 2073-4409. PMC 8699936. PMID 34944021.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ "Hep G2 [HEPG2] | ATCC". www.atcc.org. Retrieved 2022-03-01.
- ^ a b c d Burmeister, Amanda R.; Marriott, Ian (2018). "The Interleukin-10 Family of Cytokines and Their Role in the CNS". Frontiers in Cellular Neuroscience. 12. doi:10.3389/fncel.2018.00458/full. ISSN 1662-5102.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Xu, Xiaofei; Prens, Errol; Florencia, Edwin; Leenen, Pieter; Boon, Luis; Asmawidjaja, Patrick; Mus, Anne-Marie; Lubberts, Erik (2021). "Interleukin-17A Drives IL-19 and IL-24 Expression in Skin Stromal Cells Regulating Keratinocyte Proliferation". Frontiers in Immunology. 12: 719562. doi:10.3389/fimmu.2021.719562. ISSN 1664-3224. PMC 8488340. PMID 34616394.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ von Stebut, Esther; Boehncke, Wolf-Henning; Ghoreschi, Kamran; Gori, Tommaso; Kaya, Ziya; Thaci, Diamant; Schäffler, Andreas (2020). "IL-17A in Psoriasis and Beyond: Cardiovascular and Metabolic Implications". Frontiers in Immunology. 10. doi:10.3389/fimmu.2019.03096/full. ISSN 1664-3224.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ a b c García, Marcial; Jiménez-Sousa, María A.; Blanco, Julià; Restrepo, Clara; Pacheco, Yolanda M.; Brochado-Kith, Óscar; López-Bernaldo, Juan Carlos; Gutiérrez, Félix; Portilla, Joaquín; Estrada, Vicente; Górgolas, Miguel (2019-10). "CD4 recovery is associated with genetic variation in IFNγ and IL19 genes". Antiviral Research. 170: 104577. doi:10.1016/j.antiviral.2019.104577. ISSN 1872-9096. PMID 31386862.
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