| Interferon type III (λ) | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| Symbol | IL28A | ||||||||
| Pfam | PF15177 | ||||||||
| InterPro | IPR029177 | ||||||||
| CATH | 3og6A00 | ||||||||
| |||||||||
The type III interferon group is a group of anti-viral cytokines, that consists of four IFN-λ (lambda) molecules called IFN-λ1, IFN-λ2, IFN-λ3 (also known as IL29, IL28A and IL28B respectively), and IFN-λ4. [1] They were discovered in 2003. [2] Their function is similar to that of type I interferons, but is less intense and serves mostly as a first-line defence against viruses in the epithelium. [3]
Genomic location edit
Genes encoding this group of interferons are all located on the long arm of chromosome 19 in human, specifically in region between 19q13.12 and 19q13.13. IFNL1 gene, encoding IL-29, is located downstream of IFNL2, encoding IL-28A. IFNL3, encoding IL28B, is located downstream of IFNL4. [4] [5]
In mice, the genes encoding for type III interferons are located on chromosome 7 and the family consist of IFN-λ2 and IFN-λ3. [6]
Structure edit
Interferons edit
All interferon groups belong to class II cytokine family which have a conserved structure that comprises of six α-helices. [7] The proteins of type III interferon group are highly homologous and show high amino acid sequence similarity between. The similarity between IFN-λ2 and IFN-λ3 is approximately 96%, similarity of IFNλ1 to IFNλ 2/3 is around 81%. [8] Lowest similarity is found between IFN-λ4 and IFN-λ3 - only around 30%.[9][10] Unlike type I interferon group, which consist of only one exon, type III interferons consist of multiple exons. [6][11]
Receptor edit
The receptors for these cytokines are also structurally conserved. The receptors have two type III fibronectin domains in their extracellular domain. The interface of these two domains forms the cytokine binding site. [7] The receptor complex for type III interferons consists of two subunits - IL10RB (also called IL10R2 or CRF2-4) and IFNLR1 (formerly called IL28RA , CRF2-12). [12] In contrast to the ubiquitous expression of receptors for type I interferons, IFNLR1 is largely restricted to tissues of epithelial origin.[13][14][6] Despite high homology between type III interferons, the binding affinity to IFNLR1 differ, with IFN-λ1 showing the highest binding affinity, and IFN-λ3 showing the lowest binding affinity. [15]
Signaling pathway edit
IFN-λ production is induced by pathogen sensing through pattern recognition receptors (PRR), including TLR, Ku70 and RIG-1-like. The main producer of IFN-λ are type 2 myeloid dendritic cells. [11]
IFN-λ binds to IFNLR1 with a high affinity, which then recruits the low-affinity subunit of the receptor, IL10Rb. This interaction creates a signalling complex. [6] Upon binding of the cytokine to the receptor, JAK-STAT signalling pathway gets activated, specifically JAK1 and TYK2 and phosphorylate and activate STAT-1 and STAT-2, which then induces downstream signaling that leads to induction of expression of hundreds of IFN-stimulated genes (ISG), e.g.: NF-kB, IRF, ISRE, Mx1, OAS1. [11]
The signaling is modulated by supressor of cytokine signalling 1 (SOCS1) and ubiquitin-specific peptidase 18 (USP18).[11]
Function edit
Function of type III interferons seems to be similar to that of type I interferons. Both of these cytokine groups modulate the immune response after a pathogen has been sensed in the organism, their functions are mostly are anti-viral and anti-proliferative. However, type III interferons tend to be less potent, less inflammatory and show a slower kinetics than type I. Also, because of the restricted expression of IFNLR1, the immunomodulatory effect of type III interferons is limited. [6] [16]
Because the receptors for type I and type II interferons are expressed on almost all nucleated cells, their function is rather systematic, however type III interferon receptors are expressed on epithelial cells, therefore their antiviral effects are most prominent in barriers, in gastrointestinal, respiratory and reproductive tracts, so type III interferons usually act as the first line of defence against viruses at the barriers. [3][17]
In the gastrointestinal tract, type III interferons restrict the initial replication of reovirus and diminish the shedding of the virus through feces, while type I interferons prevent the systematic infection. On the other hand, in the respiratory tract these two groups of interferons seem to be rather redundant, as documented by the susceptibility of double-deficient mice (in receptors for type I and type III interferons), but the resistance to respiratory virus in mice that are deficient in either type I or type III interferon receptors. [16]
- ^ Vilcek J (January 2003). "Novel interferons". Nature Immunology. 4 (1): 8–9. doi:10.1038/ni0103-8. PMID 12496969.
- ^ Kotenko, Sergei V.; Gallagher, Grant; Baurin, Vitaliy V.; Lewis-Antes, Anita; Shen, Meiling; Shah, Nital K.; Langer, Jerome A.; Sheikh, Faruk; Dickensheets, Harold; Donnelly, Raymond P. (2002-12-16). "IFN-λs mediate antiviral protection through a distinct class II cytokine receptor complex". Nature Immunology. 4 (1): 69–77. doi:10.1038/ni875. ISSN 1529-2908.
- ^ a b Kotenko, Sergei V.; Durbin, Joan E. (2017-05-05). "Contribution of type III interferons to antiviral immunity: location, location, location". The Journal of Biological Chemistry. 292 (18): 7295–7303. doi:10.1074/jbc.R117.777102. ISSN 0021-9258. PMC 5418032. PMID 28289095.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Zhou, Jian-hua; Wang, Yi-ning; Chang, Qiu-yan; Ma, Peng; Hu, Yonghao; Cao, Xin (2018). "Type III Interferons in Viral Infection and Antiviral Immunity". Cellular Physiology and Biochemistry. 51 (1): 173–185. doi:10.1159/000495172. ISSN 1015-8987. PMID 30439714.
- ^ Syedbasha, Mohammedyaseen; Egli, Adrian (2017-02-28). "Interferon Lambda: Modulating Immunity in Infectious Diseases". Frontiers in Immunology. 8. doi:10.3389/fimmu.2017.00119. ISSN 1664-3224. PMC 5328987. PMID 28293236.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ a b c d e Lazear, Helen M.; Schoggins, John W.; Diamond, Michael S. (2019-04-16). "Shared and Distinct Functions of Type I and Type III Interferons". Immunity. 50 (4): 907–923. doi:10.1016/j.immuni.2019.03.025. ISSN 1074-7613. PMC 6839410. PMID 30995506.
- ^ a b Renauld, Jean-Christophe (2003-08). "Class II cytokine receptors and their ligands: Key antiviral and inflammatory modulators". Nature Reviews Immunology. 3 (8): 667–676. doi:10.1038/nri1153. ISSN 1474-1741.
{{cite journal}}: Check date values in:|date=(help) - ^ Kotenko, Sergei V.; Gallagher, Grant; Baurin, Vitaliy V.; Lewis-Antes, Anita; Shen, Meiling; Shah, Nital K.; Langer, Jerome A.; Sheikh, Faruk; Dickensheets, Harold; Donnelly, Raymond P. (2002-12-16). "IFN-λs mediate antiviral protection through a distinct class II cytokine receptor complex". Nature Immunology. 4 (1): 69–77. doi:10.1038/ni875. ISSN 1529-2908.
- ^ O'Brien, Thomas R.; Prokunina-Olsson, Ludmila; Donnelly, Raymond P. (2014-11). "IFN-λ4: The Paradoxical New Member of the Interferon Lambda Family". Journal of Interferon & Cytokine Research. 34 (11): 829–838. doi:10.1089/jir.2013.0136. ISSN 1079-9907.
{{cite journal}}: Check date values in:|date=(help) - ^ Fox, Brian A.; Sheppard, Paul O.; O'Hara, Patrick J. (2009-03-20). "The Role of Genomic Data in the Discovery, Annotation and Evolutionary Interpretation of the Interferon-Lambda Family". PLOS ONE. 4 (3): e4933. doi:10.1371/journal.pone.0004933. ISSN 1932-6203. PMC 2654155. PMID 19300512.
{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link) - ^ a b c d Syedbasha, Mohammedyaseen; Egli, Adrian (2017-02-28). "Interferon Lambda: Modulating Immunity in Infectious Diseases". Frontiers in Immunology. 8. doi:10.3389/fimmu.2017.00119. ISSN 1664-3224. PMC 5328987. PMID 28293236.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Bartlett NW, Buttigieg K, Kotenko SV, Smith GL (June 2005). "Murine interferon lambdas (type III interferons) exhibit potent antiviral activity in vivo in a poxvirus infection model". The Journal of General Virology. 86 (Pt 6): 1589–96. doi:10.1099/vir.0.80904-0. PMID 15914836.
- ^ Kotenko SV, Gallagher G, Baurin VV, Lewis-Antes A, Shen M, Shah NK, et al. (January 2003). "IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex". Nature Immunology. 4 (1): 69–77. doi:10.1038/ni875. PMID 12483210.
- ^ Sheppard P, Kindsvogel W, Xu W, Henderson K, Schlutsmeyer S, Whitmore TE, et al. (January 2003). "IL-28, IL-29 and their class II cytokine receptor IL-28R". Nature Immunology. 4 (1): 63–8. doi:10.1038/ni873. PMID 12469119.
- ^ Fox, Brian A.; Sheppard, Paul O.; O'Hara, Patrick J. (2009-03-20). "The Role of Genomic Data in the Discovery, Annotation and Evolutionary Interpretation of the Interferon-Lambda Family". PLOS ONE. 4 (3): e4933. doi:10.1371/journal.pone.0004933. ISSN 1932-6203. PMC 2654155. PMID 19300512.
{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link) - ^ a b Wack, Andreas; Terczyńska-Dyla, Ewa; Hartmann, Rune (2015). "Guarding the frontiers: the biology of type III interferons". Nature Immunology. 16 (8): 802–809. doi:10.1038/ni.3212. ISSN 1529-2908. PMC 7096991. PMID 26194286.
- ^ Lazear, Helen M.; Nice, Timothy J.; Diamond, Michael S. (2015-07-21). "Interferon-λ: Immune Functions at Barrier Surfaces and Beyond". Immunity. 43 (1): 15–28. doi:10.1016/j.immuni.2015.07.001. ISSN 1074-7613. PMC 4527169. PMID 26200010.
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