Interleukin 35 Explained

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.

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.[2] [3] 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.[4] On regulatory B-cells, IL-35 signals through the IL-12Rβ2 and IL-27Rα subunits.[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.[7] [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]

Notes and References

  1. Behzadi P, Behzadi E, Ranjbar R . IL-12 Family Cytokines: General Characteristics, Pathogenic Microorganisms, Receptors, and Signalling Pathways . Acta Microbiologica et Immunologica Hungarica . 63 . 1 . 1–25 . March 2016 . 27020866 . 10.1556/030.63.2016.1.1 .
  2. Li X, Fang P, Yang WY, Wang H, Yang X . 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 . October 2019 . 28648331 . 5741534 . 10.1016/j.cyto.2017.06.003 .
  3. Su LC, Liu XY, Huang AF, Xu WD . Emerging role of IL-35 in inflammatory autoimmune diseases . Autoimmunity Reviews . 17 . 7 . 665–673 . July 2018 . 29729445 . 10.1016/j.autrev.2018.01.017 . 19146526 .
  4. Collison LW, Delgoffe GM, Guy CS, Vignali KM, Chaturvedi V, Fairweather D, Satoskar AR, Garcia KC, Hunter CA, Drake CG, Murray PJ, Vignali DA . 6 . The composition and signaling of the IL-35 receptor are unconventional . Nature Immunology . 13 . 3 . 290–9 . February 2012 . 22306691 . 3529151 . 10.1038/ni.2227 .
  5. Wang RX, Yu CR, Dambuza IM, Mahdi RM, Dolinska MB, Sergeev YV, Wingfield PT, Kim SH, Egwuagu CE . 6 . Interleukin-35 induces regulatory B cells that suppress autoimmune disease . Nature Medicine . 20 . 6 . 633–41 . June 2014 . 24743305 . 4048323 . 10.1038/nm.3554 .
  6. Devergne O, Hummel M, Koeppen H, Le Beau MM, Nathanson EC, Kieff E, Birkenbach M . A novel interleukin-12 p40-related protein induced by latent Epstein-Barr virus infection in B lymphocytes . Journal of Virology . 70 . 2 . 1143–53 . February 1996 . 8551575 . 189923 . 10.1128/JVI.70.2.1143-1153.1996 .
  7. Shen P, Roch T, Lampropoulou V, O'Connor RA, Stervbo U, Hilgenberg E, Ries S, Dang VD, Jaimes Y, Daridon C, Li R, Jouneau L, Boudinot P, Wilantri S, Sakwa I, Miyazaki Y, Leech MD, McPherson RC, Wirtz S, Neurath M, Hoehlig K, Meinl E, Grützkau A, Grün JR, Horn K, Kühl AA, Dörner T, Bar-Or A, Kaufmann SH, Anderton SM, Fillatreau S . 6 . IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases . Nature . 507 . 7492 . 366–370 . March 2014 . 24572363 . 4260166 . 10.1038/nature12979 . 2014Natur.507..366S .
  8. Olson BM, Jankowska-Gan E, Becker JT, Vignali DA, Burlingham WJ, McNeel DG . 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 . December 2012 . 23152566 . 3735346 . 10.4049/jimmunol.1201744 .
  9. Li X, Shao Y, Sha X, Fang P, Kuo YM, Andrews AJ, Li Y, Yang WY, Maddaloni M, Pascual DW, Luo JJ, Jiang X, Wang H, Yang X . 6 . 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 . March 2018 . 29371247 . 5823772 . 10.1161/ATVBAHA.117.310626 .
  10. Li X, Mai J, Virtue A, Yin Y, Gong R, Sha X, Gutchigian S, Frisch A, Hodge I, Jiang X, Wang H, Yang XF . 6 . IL-35 is a novel responsive anti-inflammatory cytokine--a new system of categorizing anti-inflammatory cytokines . PLOS ONE . 7 . 3 . e33628 . March 2012 . 22438968 . 3306427 . 10.1371/journal.pone.0033628 . 2012PLoSO...733628L . free .
  11. Niedbala W, Wei XQ, Cai B, Hueber AJ, Leung BP, McInnes IB, Liew FY . 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 . November 2007 . 17874423 . 10.1002/eji.200737810 . 38306559 .
  12. Collison LW, Workman CJ, Kuo TT, Boyd K, Wang Y, Vignali KM, Cross R, Sehy D, Blumberg RS, Vignali DA . 6 . The inhibitory cytokine IL-35 contributes to regulatory T-cell function . Nature . 450 . 7169 . 566–9 . November 2007 . 18033300 . 10.1038/nature06306 . 2007Natur.450..566C . 4425281 .
  13. Wu S, Li Y, Li Y, Yao L, Lin T, Jiang S, Shen H, Xia L, Lu J . 6 . Interleukin-35 attenuates collagen-induced arthritis through suppression of vascular endothelial growth factor and its receptors . International Immunopharmacology . 34 . 71–77 . May 2016 . 26922678 . 10.1016/j.intimp.2016.02.018 .
  14. Wu S, Li Y, Yao L, Li Y, Jiang S, Gu W, Shen H, Xia L, Lu J . 6 . Interleukin-35 inhibits angiogenesis through STAT1 signalling in rheumatoid synoviocytes . Clinical and Experimental Rheumatology . 36 . 2 . 223–227 . March 2018 . 28850026 .
  15. Vignali DA, Kuchroo VK . IL-12 family cytokines: immunological playmakers . Nature Immunology . 13 . 8 . 722–8 . July 2012 . 22814351 . 4158817 . 10.1038/ni.2366 .
  16. Sun L, He C, Nair L, Yeung J, Egwuagu CE . Interleukin 12 (IL-12) family cytokines: Role in immune pathogenesis and treatment of CNS autoimmune disease . Cytokine . 75 . 2 . 249–55 . October 2015 . 25796985 . 4553122 . 10.1016/j.cyto.2015.01.030 .
  17. Singh K, Kadesjö E, Lindroos J, Hjort M, Lundberg M, Espes D, Carlsson PO, Sandler S, Thorvaldson L . 6 . Interleukin-35 administration counteracts established murine type 1 diabetes--possible involvement of regulatory T cells . Scientific Reports . 5 . 1 . 12633 . July 2015 . 26224624 . 4519737 . 10.1038/srep12633 . 2015NatSR...512633S .
  18. Espes D, Singh K, Sandler S, Carlsson PO . Increased Interleukin-35 Levels in Patients With Type 1 Diabetes With Remaining C-Peptide . Diabetes Care . 40 . 8 . 1090–1095 . August 2017 . 28620093 . 10.2337/dc16-2121 . 207367998 . free .
  19. Tao NN, Gong R, Chen X, He L, Ren F, Yu HB, Chen J, Ren JH . 6 . Interleukin-35 stimulates hepatitis B virus transcription and replication by targeting transcription factor HNF4α . The Journal of General Virology . 99 . 5 . 645–654 . May 2018 . 29561254 . 10.1099/jgv.0.001050 . free .
  20. Sawant DV, Hamilton K, Vignali DA . Interleukin-35: Expanding Its Job Profile . Journal of Interferon & Cytokine Research . 35 . 7 . 499–512 . July 2015 . 25919641 . 4507123 . 10.1089/jir.2015.0015 .
  21. Wu H, Li P, Shao N, Ma J, Ji M, Sun X, Ma D, Ji C . 6 . 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 . May 2012 . 22783403 . 3389635 . 10.3892/ol.2012.614 .
  22. Jin P, Ren H, Sun W, Xin W, Zhang H, Hao J . Circulating IL-35 in pancreatic ductal adenocarcinoma patients . Human Immunology . 75 . 1 . 29–33 . January 2014 . 24121041 . 10.1016/j.humimm.2013.09.018 .
  23. Zeng JC, Zhang Z, Li TY, Liang YF, Wang HM, Bao JJ, Zhang JA, Wang WD, Xiang WY, Kong B, Wang ZY, Wu BH, Chen XD, He L, Zhang S, Wang CY, Xu JF . 6 . Assessing the role of IL-35 in colorectal cancer progression and prognosis . International Journal of Clinical and Experimental Pathology . 6 . 9 . 1806–16 . 2013-08-15 . 24040445 . 3759487 .
  24. Ezzeddini R, Somi MH, Taghikhani M, Moaddab SY, Masnadi Shirazi K, Shirmohammadi M, Eftekharsadat AT, Sadighi Moghaddam B, Salek Farrokhi A . Association of Foxp3 rs3761548 polymorphism with cytokines concentration in gastric adenocarcinoma patients . Cytokine . 138 . 155351 . February 2021 . 33127257 . 10.1016/j.cyto.2020.155351 . 226218796 . 1043-4666 .

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