Interleukin 35

Interleukin 35 (IL-35) is a recently discovered anti-infl ammatory cytokine from the IL-12 family. Member of IL-12 family - IL-35 is produced by wide range of regulatory lymphocytes and plays a role in immune suppression.[1] IL-35 can block the development of Th1 and Th17 cells by limiting early T cell proliferation.[2]

"IL-35" redirects here. For the road, see Illinois Route 35.

Structure

IL-35 and its receptor

IL-35 is a dimeric protein composed of IL-12α and IL-27β chains, which are encoded by two separate genes called IL12A and EBI3 (Epstein-Barr virus-induced gene 3), respectively.[3][4] IL-35 receptor consists of IL-12Rβ2 (part of the IL-12R) and gp130 (part of IL-27R) chains. Compared to these two related interleukins, IL-35 is also able to signal through only one of the aforementioned chains. This was proven in vivo when absence of either of the receptor chains did not influence effects of IL-35.[5]

EBI3 is a homologue to IL-12 p40 and to the ciliary neurotrophic factor receptor, whose expression is induced in B lymphoblastoid cells by EBV infection[6]

Function

Expression

Secreted by regulatory T-cells (Tregs), regulatory B-cells (Bregs)[7] or even CD8+ regulatory T cells,[8] IL-35 suppresses inflammatory responses of immune cells.[9] IL-35 is not constitutively expressed in tissues, but the gene encoding IL-35 is transcribed by vascular endothelial cells, smooth muscle cells and monocytes after activation with proinflammatory stimuli.[10] IL-35 has selective activities on different T-cell subsets; it induces proliferation of Treg cell populations but reduces activity of Th17 cell populations.[11]

Role in disease

Autoimmune conditions

Studies in mice show the absence of either IL-35 chain from regulatory Tregs reduces the cells' ability to suppress inflammation. This has been observed during cell culture experiments and using an experimental model for inflammatory bowel disease.[12] A group of scientists established a CIA (collagen-induced arthritis) mouse model to show suppressive effects of IL-35. Intraperitoneal injection of IL-35 in the tested subjects lowered expression of several factors linked to this disease (such as VEGF and its receptors, TNF-α).[13] The effect of IL-35 in this case seems to be the inhibition of STAT1 signalling pathway.[14] Another experiment performed on a mouse model of EAE has shown, that mice lacking IL-35-producing B cells are unable to recover from the T-cell mediated demyelination but are resistant to infection by pathogenic intracellular microbe Salmonella typhimurium.[15][16][17]

Infectious diseases

It has been shown that IL-35 increases replication of HBV virus both in vitro and in transgenic mice by targeting its transcription factor HNF4α.[18]

References
  1. Behzadi P, Behzadi E, Ranjbar R (March 2016). "IL-12 Family Cytokines: General Characteristics, Pathogenic Microorganisms, Receptors, and Signalling Pathways" (PDF). Acta Microbiologica et Immunologica Hungarica. 63 (1): 1–25. doi:10.1556/030.63.2016.1.1. PMID 27020866.
  2. Collison LW, Workman CJ, Kuo TT, Boyd K, Wang Y, Vignali KM, et al. (November 2007). "The inhibitory cytokine IL-35 contributes to regulatory T-cell function". Nature. 450 (7169): 566–9. Bibcode:2007Natur.450..566C. doi:10.1038/nature06306. PMID 18033300.
  3. Li X, Fang P, Yang WY, Wang H, Yang X (October 2019). "IL-35, as a newly proposed homeostasis-associated molecular pattern, plays three major functions including anti-inflammatory initiator, effector, and blocker in cardiovascular diseases". Cytokine. 122: 154076. doi:10.1016/j.cyto.2017.06.003. PMC 5741534. PMID 28648331.
  4. Su LC, Liu XY, Huang AF, Xu WD (July 2018). "Emerging role of IL-35 in inflammatory autoimmune diseases". Autoimmunity Reviews. 17 (7): 665–673. doi:10.1016/j.autrev.2018.01.017. PMID 29729445.
  5. Collison LW, Delgoffe GM, Guy CS, Vignali KM, Chaturvedi V, Fairweather D, et al. (February 2012). "The composition and signaling of the IL-35 receptor are unconventional". Nature Immunology. 13 (3): 290–9. doi:10.1038/ni.2227. PMC 3529151. PMID 22306691.
  6. Devergne O, Hummel M, Koeppen H, Le Beau MM, Nathanson EC, Kieff E, Birkenbach M (February 1996). "A novel interleukin-12 p40-related protein induced by latent Epstein-Barr virus infection in B lymphocytes". Journal of Virology. 70 (2): 1143–53. doi:10.1128/JVI.70.2.1143-1153.1996. PMC 189923. PMID 8551575.
  7. Shen P, Roch T, Lampropoulou V, O'Connor RA, Stervbo U, Hilgenberg E, et al. (March 2014). "IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases". Nature. 507 (7492): 366–370. Bibcode:2014Natur.507..366S. doi:10.1038/nature12979. PMC 4260166. PMID 24572363.
  8. Olson BM, Jankowska-Gan E, Becker JT, Vignali DA, Burlingham WJ, McNeel DG (December 2012). "Human prostate tumor antigen-specific CD8+ regulatory T cells are inhibited by CTLA-4 or IL-35 blockade". Journal of Immunology. 189 (12): 5590–601. doi:10.4049/jimmunol.1201744. PMC 3735346. PMID 23152566.
  9. Li X, Shao Y, Sha X, Fang P, Kuo YM, Andrews AJ, et al. (March 2018). "IL-35 (Interleukin-35) Suppresses Endothelial Cell Activation by Inhibiting Mitochondrial Reactive Oxygen Species-Mediated Site-Specific Acetylation of H3K14 (Histone 3 Lysine 14)". Arteriosclerosis, Thrombosis, and Vascular Biology. 38 (3): 599–609. doi:10.1161/ATVBAHA.117.310626. PMC 5823772. PMID 29371247.
  10. Li X, Mai J, Virtue A, Yin Y, Gong R, Sha X, et al. (March 2012). "IL-35 is a novel responsive anti-inflammatory cytokine--a new system of categorizing anti-inflammatory cytokines". PLOS ONE. 7 (3): e33628. Bibcode:2012PLoSO...733628L. doi:10.1371/journal.pone.0033628. PMC 3306427. PMID 22438968.
  11. Niedbala W, Wei XQ, Cai B, Hueber AJ, Leung BP, McInnes IB, Liew FY (November 2007). "IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells". European Journal of Immunology. 37 (11): 3021–9. doi:10.1002/eji.200737810. PMID 17874423.
  12. Collison LW, Workman CJ, Kuo TT, Boyd K, Wang Y, Vignali KM, et al. (November 2007). "The inhibitory cytokine IL-35 contributes to regulatory T-cell function". Nature. 450 (7169): 566–9. Bibcode:2007Natur.450..566C. doi:10.1038/nature06306. PMID 18033300.
  13. Wu S, Li Y, Li Y, Yao L, Lin T, Jiang S, et al. (May 2016). "Interleukin-35 attenuates collagen-induced arthritis through suppression of vascular endothelial growth factor and its receptors". International Immunopharmacology. 34: 71–77. doi:10.1016/j.intimp.2016.02.018. PMID 26922678.
  14. Wu S, Li Y, Yao L, Li Y, Jiang S, Gu W, et al. (March 2018). "Interleukin-35 inhibits angiogenesis through STAT1 signalling in rheumatoid synoviocytes". Clinical and Experimental Rheumatology. 36 (2): 223–227. PMID 28850026.
  15. Shen P, Roch T, Lampropoulou V, O'Connor RA, Stervbo U, Hilgenberg E, et al. (March 2014). "IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases". Nature. 507 (7492): 366–370. Bibcode:2014Natur.507..366S. doi:10.1038/nature12979. PMC 4260166. PMID 24572363.
  16. Vignali DA, Kuchroo VK (July 2012). "IL-12 family cytokines: immunological playmakers". Nature Immunology. 13 (8): 722–8. doi:10.1038/ni.2366. PMC 4158817. PMID 22814351.
  17. Sun L, He C, Nair L, Yeung J, Egwuagu CE (October 2015). "Interleukin 12 (IL-12) family cytokines: Role in immune pathogenesis and treatment of CNS autoimmune disease". Cytokine. 75 (2): 249–55. doi:10.1016/j.cyto.2015.01.030. PMC 4553122. PMID 25796985.
  18. Tao NN, Gong R, Chen X, He L, Ren F, Yu HB, et al. (May 2018). "Interleukin-35 stimulates hepatitis B virus transcription and replication by targeting transcription factor HNF4α". The Journal of General Virology. 99 (5): 645–654. doi:10.1099/jgv.0.001050. PMID 29561254.
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