Interleukin 35

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Interleukin 35 (IL-35) is a recently discovered cytokine from the IL-12 family. IL-35 is produced by wide range of regulatory lymphocytes and plays a role in immune suppression.


IL-35 and its receptor[edit]

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, respectively.[1] 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.[2]



Secreted by regulatory T-cells (Tregs), regulatory B-cells (Bregs)[3] or even CD8+ regulatory T cells,[4] IL-35 suppresses inflammatory responses of immune cells.[5] 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.[6] IL-35 has selective activities on different T-cell subsets; it induces proliferation of Treg cell populations but reduces activity of Th17 cell populations.[7]

Role in disease[edit]

Autoimmune conditions[edit]

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.[8] 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).[9] The effect of IL-35 in this case seems to be the inhibition of STAT1 signalling pathway.[10] 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.[11]

Infectious diseases[edit]

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.[12]


  1. ^ Li X, Fang P, Yang WY, Wang H, Yang X (June 2017). "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. doi:10.1016/j.cyto.2017.06.003. PMC 5741534. PMID 28648331.
  2. ^ Collison LW, Delgoffe GM, Guy CS, Vignali KM, Chaturvedi V, Fairweather D, Satoskar AR, Garcia KC, Hunter CA, Drake CG, Murray PJ, Vignali DA (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.
  3. ^ 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. doi:10.1038/nature12979. PMC 4260166. PMID 24572363.
  4. ^ 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.
  5. ^ 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.
  6. ^ Li X, Mai J, Virtue A, Yin Y, Gong R, Sha X, Gutchigian S, Frisch A, Hodge I, Jiang X, Wang H, Yang XF (March 2012). "IL-35 is a novel responsive anti-inflammatory cytokine--a new system of categorizing anti-inflammatory cytokines". PLOS One. 7 (3): e33628. doi:10.1371/journal.pone.0033628. PMC 3306427. PMID 22438968.
  7. ^ 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.
  8. ^ Collison LW, Workman CJ, Kuo TT, Boyd K, Wang Y, Vignali KM, Cross R, Sehy D, Blumberg RS, Vignali DA (November 2007). "The inhibitory cytokine IL-35 contributes to regulatory T-cell function". Nature. 450 (7169): 566–9. doi:10.1038/nature06306. PMID 18033300.
  9. ^ Wu S, Li Y, Li Y, Yao L, Lin T, Jiang S, Shen H, Xia L, Lu J (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.
  10. ^ Wu, Suqin; Li, Yuxuan; Yao, Lutian; Li, Yunxia; Jiang, Shenyi; Gu, Wei; Shen, Hui; Xia, Liping; Lu, Jing (March 2018). "Interleukin-35 inhibits angiogenesis through STAT1 signalling in rheumatoid synoviocytes". Clinical and Experimental Rheumatology. 36 (2): 223–227. ISSN 0392-856X. PMID 28850026.
  11. ^ 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. doi:10.1038/nature12979. PMC 4260166. PMID 24572363.
  12. ^ Tao, Na-Na; Gong, Rui; Chen, Xiang; He, Lin; Ren, Fang; Yu, Hai-Bo; Chen, Juan; Ren, Ji-Hua (2018). "Interleukin-35 stimulates hepatitis B virus transcription and replication by targeting transcription factor HNF4α". Journal of General Virology. 99 (5): 645–654. doi:10.1099/jgv.0.001050.