Interleukin 29 Explained

Interleukin-29 (IL-29) is a cytokine and it belongs to type III interferons group, also termed interferons λ (IFN-λ). IL-29 (alternative name IFNλ1) plays an important role in the immune response against pathogenes and especially against viruses by mechanisms similar to type I interferons, but targeting primarily cells of epithelial origin and hepatocytes.^{[1] [2]}

IL-29 is encoded by the IFNL1 gene located on chromosome 19 in humans.^[3] It is a pseudogene in mice meaning the IL-29 protein is not produced in them.

Structure

IL-29 is, with the rest of IFN-λ, structurally related to the IL-10 family, but its primary amino acid sequence (and also function) is more similar to type I interferons. It binds to a heterodimeric receptor composed of one subunit IFNL1R specific for IFN-λ and a second subunit IL10RB shared among the IL-10 family cytokines.

Function

Effects on immune response to pathogens  

IL-29 exhibits antiviral effects by inducing similar signaling pathways as type I interferons. IL-29 receptor signals through JAK-STAT pathways leading to activated expression of interferon-stimulated genes and production of antiviral proteins.^[4] Further consequences of IL-29 signalization comprise the upregulated expression of MHC class I molecules, or enhanced expression of the costimulatory molecules and chemokine receptors on pDC, which are the main producers of IFN-α.

IL-29 expression is dominant in virus-infected epithelial cells of the respiratory, gastrointestinal and urogenital tracts, also in other mucosal tissues and skin. Hepatocytes infected by HCV or HBV viruses stimulate the immune response by producing IL-29 (IFN-λ in general) rather than type I interferons. It is also produced by maturing macrophages, dendritic cells or mastocytes.

It plays a role in defense against pathogens apart from viruses. It affects the function of both innate and adaptive immune system. Besides described antiviral effects, IL-29 modulates cytokine production of other cells, for example, it increases secretion of IL-6, IL-8 and IL-10 by monocytes and macrophages, enhances the responsiveness of macrophages to IFN-γ by increased expression of IFNGR1, stimulates T cell polarization towards Th1 phenotype and also B cell response to IL-29 was reported.

Antitumor immunity

The impact of IL-29 on cancer cells is complicated depending on cancer cell type. It shows protective tumor inhibiting effects in many cases such as skin, lung, colorectal or hepatocellular cancer, but shows tumor promoting effects on multiple myeloma cells. IFN-λ have potential as cancer therapy, with effects on more restricted cell types and fewer side-effects than type I interferons.

Autoimmune diseases

Abnormal expression of IL-29 could be involved in the pathogenesis of the autoimmune diseases by enhancing the production of inflammatory cytokines, chemokines, and other autoimmune‐related components. High levels of IL-29 in serum or disease-specific tissue was observed in patients with rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, Sjögren's syndrome, psoriasis, atopic dermatitis, Hashimoto's thyroiditis, systemic sclerosis and uveitis.

Further reading

• Pagliaccetti NE, Eduardo R, Kleinstein SH, Mu XJ, Bandi P, Robek MD . Interleukin-29 functions cooperatively with interferon to induce antiviral gene expression and inhibit hepatitis C virus replication . The Journal of Biological Chemistry . 283 . 44 . 30079–89 . October 2008 . 18757365 . 2662072 . 10.1074/jbc.M804296200 . free .
• Li MC, Wang HY, Wang HY, Li T, He SH . Liposome-mediated IL-28 and IL-29 expression in A549 cells and anti-viral effect of IL-28 and IL-29 on WISH cells . Acta Pharmacologica Sinica . 27 . 4 . 453–9 . April 2006 . 16539846 . 10.1111/j.1745-7254.2006.00292.x . free .
• Megjugorac NJ, Gallagher GE, Gallagher G . Modulation of human plasmacytoid DC function by IFN-lambda1 (IL-29) . Journal of Leukocyte Biology . 86 . 6 . 1359–63 . December 2009 . 19759281 . 10.1189/jlb.0509347 . 22453858 . free .
• Uzé G, Monneron D . IL-28 and IL-29: newcomers to the interferon family . Biochimie . 89 . 6–7 . 729–34 . 2007 . 17367910 . 10.1016/j.biochi.2007.01.008 .
• Hou W, Wang X, Ye L, Zhou L, Yang ZQ, Riedel E, Ho WZ . Lambda interferon inhibits human immunodeficiency virus type 1 infection of macrophages . Journal of Virology . 83 . 8 . 3834–42 . April 2009 . 19193806 . 2663280 . 10.1128/JVI.01773-08 .
• Magracheva E, Pletnev S, Kotenko S, Li W, Wlodawer A, Zdanov A . Purification, crystallization and preliminary crystallographic studies of the complex of interferon-lambda1 with its receptor . Acta Crystallographica Section F . 66 . Pt 1 . 61–3 . January 2010 . 20057073 . 2805539 . 10.1107/S1744309109048817 .
• Stoltz M, Klingström J . Alpha/beta interferon (IFN-alpha/beta)-independent induction of IFN-lambda1 (interleukin-29) in response to Hantaan virus infection . Journal of Virology . 84 . 18 . 9140–8 . September 2010 . 20592090 . 2937636 . 10.1128/JVI.00717-10 .
• Brand S, Beigel F, Olszak T, Zitzmann K, Eichhorst ST, Otte JM, Diebold J, Diepolder H, Adler B, Auernhammer CJ, Göke B, Dambacher J . IL-28A and IL-29 mediate antiproliferative and antiviral signals in intestinal epithelial cells and murine CMV infection increases colonic IL-28A expression . American Journal of Physiology. Gastrointestinal and Liver Physiology . 289 . 5 . G960–8 . November 2005 . 16051921 . 10.1152/ajpgi.00126.2005 . 25466268 .
• Pekarek V, Srinivas S, Eskdale J, Gallagher G . Interferon lambda-1 (IFN-lambda1/IL-29) induces ELR(-) CXC chemokine mRNA in human peripheral blood mononuclear cells, in an IFN-gamma-independent manner . Genes and Immunity . 8 . 2 . 177–80 . March 2007 . 17252004 . 10.1038/sj.gene.6364372 . free .
• Li M, Liu X, Zhou Y, Su SB . Interferon-lambdas: the modulators of antivirus, antitumor, and immune responses . Journal of Leukocyte Biology . 86 . 1 . 23–32 . July 2009 . 19304895 . 10.1189/jlb.1208761 . 37741272 . free .
• Jordan WJ, Eskdale J, Boniotto M, Rodia M, Kellner D, Gallagher G . Modulation of the human cytokine response by interferon lambda-1 (IFN-lambda1/IL-29) . Genes and Immunity . 8 . 1 . 13–20 . January 2007 . 17082759 . 10.1038/sj.gene.6364348 . 40259925 .
• Wang J, Oberley-Deegan R, Wang S, Nikrad M, Funk CJ, Hartshorn KL, Mason RJ . Differentiated human alveolar type II cells secrete antiviral IL-29 (IFN-lambda 1) in response to influenza A infection . Journal of Immunology . 182 . 3 . 1296–304 . February 2009 . 19155475 . 4041086 . 10.4049/jimmunol.182.3.1296 .
• Lasfar A, Lewis-Antes A, Smirnov SV, Anantha S, Abushahba W, Tian B, Reuhl K, Dickensheets H, Sheikh F, Donnelly RP, Raveche E, Kotenko SV . Characterization of the mouse IFN-lambda ligand-receptor system: IFN-lambdas exhibit antitumor activity against B16 melanoma . Cancer Research . 66 . 8 . 4468–77 . April 2006 . 16618774 . 10.1158/0008-5472.CAN-05-3653 .
• Osterlund P, Veckman V, Sirén J, Klucher KM, Hiscott J, Matikainen S, Julkunen I . Gene expression and antiviral activity of alpha/beta interferons and interleukin-29 in virus-infected human myeloid dendritic cells . Journal of Virology . 79 . 15 . 9608–17 . August 2005 . 16014923 . 1181545 . 10.1128/JVI.79.15.9608-9617.2005 .
• Maher SG, Sheikh F, Scarzello AJ, Romero-Weaver AL, Baker DP, Donnelly RP, Gamero AM . IFNalpha and IFNlambda differ in their antiproliferative effects and duration of JAK/STAT signaling activity . Cancer Biology & Therapy . 7 . 7 . 1109–15 . July 2008 . 18698163 . 2435218 . 10.4161/cbt.7.7.6192 .
• Mennechet FJ, Uzé G . Interferon-lambda-treated dendritic cells specifically induce proliferation of FOXP3-expressing suppressor T cells . Blood . 107 . 11 . 4417–23 . June 2006 . 16478884 . 10.1182/blood-2005-10-4129 . free .
• Wolk K, Witte K, Witte E, Proesch S, Schulze-Tanzil G, Nasilowska K, Thilo J, Asadullah K, Sterry W, Volk HD, Sabat R . Maturing dendritic cells are an important source of IL-29 and IL-20 that may cooperatively increase the innate immunity of keratinocytes . Journal of Leukocyte Biology . 83 . 5 . 1181–93 . May 2008 . 18281438 . 10.1189/jlb.0807525 . 46765523 .
• Novak AJ, Grote DM, Ziesmer SC, Rajkumar V, Doyle SE, Ansell SM . A role for IFN-lambda1 in multiple myeloma B cell growth . Leukemia . 22 . 12 . 2240–6 . December 2008 . 18830264 . 2771776 . 10.1038/leu.2008.263 .
• Witte K, Gruetz G, Volk HD, Looman AC, Asadullah K, Sterry W, Sabat R, Wolk K . Despite IFN-lambda receptor expression, blood immune cells, but not keratinocytes or melanocytes, have an impaired response to type III interferons: implications for therapeutic applications of these cytokines . Genes and Immunity . 10 . 8 . 702–14 . December 2009 . 19798076 . 10.1038/gene.2009.72 . 9721683 .
• Rauch A, Kutalik Z, Descombes P, Cai T, Di Iulio J, Mueller T, Bochud M, Battegay M, Bernasconi E, Borovicka J, Colombo S, Cerny A, Dufour JF, Furrer H, Günthard HF, Heim M, Hirschel B, Malinverni R, Moradpour D, Müllhaupt B, Witteck A, Beckmann JS, Berg T, Bergmann S, Negro F, Telenti A, Bochud PY . Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study . Gastroenterology . 138 . 4 . 1338–45, 1345.e1–7 . April 2010 . 20060832 . 10.1053/j.gastro.2009.12.056 .

Notes and References

1. Lazear HM, Nice TJ, Diamond MS . Interferon-λ: Immune Functions at Barrier Surfaces and Beyond . Immunity . 43 . 1 . 15–28 . July 2015 . 26200010 . 4527169 . 10.1016/j.immuni.2015.07.001 .
2. Kelm NE, Zhu Z, Ding VA, Xiao H, Wakefield MR, Bai Q, Fang Y . The role of IL-29 in immunity and cancer . Critical Reviews in Oncology/Hematology . 106 . 91–8 . October 2016 . 27637354 . 7129698 . 10.1016/j.critrevonc.2016.08.002 .
3. Web site: Entrez Gene: interleukin 29 (interferon.
4. Wang JM, Huang AF, Xu WD, Su LC . Insights into IL-29: Emerging role in inflammatory autoimmune diseases . Journal of Cellular and Molecular Medicine . 23 . 12 . 7926–7932 . December 2019 . 31578802 . 6850914 . 10.1111/jcmm.14697 .