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

Interleukin 35 (IL-35) is a recently discovered anti-inflammatory 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]

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] On regulatory B-cells, IL-35 signals through the IL-12Rβ2 and IL-27Rα subunits. [6]

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 [7]

Function

Expression

Secreted by regulatory T-cells ( Tregs), regulatory B-cells ( Bregs) [8] or even CD8+ regulatory T cells, [9] IL-35 suppresses inflammatory responses of immune cells. [10] 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. [11] IL-35 has selective activities on different T-cell subsets; it induces proliferation of Treg cell populations but reduces activity of Th17 cell populations. [12]

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. [2] 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. [8] [15] [16] In T1D (type 1 diabetes), plasma level of IL-35 is lower than healthy individuals. IL-35 production by Tregs is decreased in mouse models of T1D, and administration of IL-35 prevents the development of experimental T1D and reverses established experimental T1D. [17] In T1D patients with remaining C-peptide, IL-35 production by Tregs and Bregs is much higher than T1D patients with no remaining C-peptide. [18]

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. [19]

Tumor

Given its suppressive function, IL-35 is also involved in tumor progression and tumor immune surveillance. [20] Elevated circulating IL-35 levels have been found in several human tumors such as acute myeloid leukemia, [21] pancreatic ductal adenocarcinoma [22] and colorectal cancer. [23]

Moreover, Forkhead box protein 3 ( Foxp3) as a transcription factor is an essential molecular marker of regulatory T ( Treg) cells. Foxp3 polymorphism (rs3761548) might be involved in cancer progression like gastric cancer through influencing Tregs function and the secretion of immunomodulatory cytokines such as IL-10, IL-35, and TGF-β. [24]

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. ^ a b 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. S2CID  4425281.
  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. S2CID  19146526.
  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. ^ Wang RX, Yu CR, Dambuza IM, Mahdi RM, Dolinska MB, Sergeev YV, et al. (June 2014). "Interleukin-35 induces regulatory B cells that suppress autoimmune disease". Nature Medicine. 20 (6): 633–41. doi: 10.1038/nm.3554. PMC  4048323. PMID  24743305.
  7. ^ 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.
  8. ^ a b 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.
  9. ^ 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.
  10. ^ 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.
  11. ^ 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.
  12. ^ 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. S2CID  38306559.
  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. ^ 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.
  16. ^ 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.
  17. ^ Singh K, Kadesjö E, Lindroos J, Hjort M, Lundberg M, Espes D, et al. (July 2015). "Interleukin-35 administration counteracts established murine type 1 diabetes--possible involvement of regulatory T cells". Scientific Reports. 5 (1): 12633. Bibcode: 2015NatSR...512633S. doi: 10.1038/srep12633. PMC  4519737. PMID  26224624.
  18. ^ Espes D, Singh K, Sandler S, Carlsson PO (August 2017). "Increased Interleukin-35 Levels in Patients With Type 1 Diabetes With Remaining C-Peptide". Diabetes Care. 40 (8): 1090–1095. doi: 10.2337/dc16-2121. PMID  28620093. S2CID  207367998.
  19. ^ 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.
  20. ^ Sawant DV, Hamilton K, Vignali DA (July 2015). "Interleukin-35: Expanding Its Job Profile". Journal of Interferon & Cytokine Research. 35 (7): 499–512. doi: 10.1089/jir.2015.0015. PMC  4507123. PMID  25919641.
  21. ^ Wu H, Li P, Shao N, Ma J, Ji M, Sun X, et al. (May 2012). "Aberrant expression of Treg-associated cytokine IL-35 along with IL-10 and TGF-β in acute myeloid leukemia". Oncology Letters. 3 (5): 1119–1123. doi: 10.3892/ol.2012.614. PMC  3389635. PMID  22783403.
  22. ^ Jin P, Ren H, Sun W, Xin W, Zhang H, Hao J (January 2014). "Circulating IL-35 in pancreatic ductal adenocarcinoma patients". Human Immunology. 75 (1): 29–33. doi: 10.1016/j.humimm.2013.09.018. PMID  24121041.
  23. ^ Zeng JC, Zhang Z, Li TY, Liang YF, Wang HM, Bao JJ, et al. (2013-08-15). "Assessing the role of IL-35 in colorectal cancer progression and prognosis". International Journal of Clinical and Experimental Pathology. 6 (9): 1806–16. PMC  3759487. PMID  24040445.
  24. ^ Ezzeddini R, Somi MH, Taghikhani M, Moaddab SY, Masnadi Shirazi K, Shirmohammadi M, Eftekharsadat AT, Sadighi Moghaddam B, Salek Farrokhi A (February 2021). "Association of Foxp3 rs3761548 polymorphism with cytokines concentration in gastric adenocarcinoma patients". Cytokine. 138: 155351. doi: 10.1016/j.cyto.2020.155351. ISSN  1043-4666. PMID  33127257. S2CID  226218796.
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