Interleukin 35

"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 (T_regs), regulatory B-cells (B_regs)^[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 T_reg cell populations but reduces activity of T_h17 cell populations.^[12]

Role in disease

Autoimmune conditions

Studies in mice show the absence of either IL-35 chain from regulatory T_regs 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 T_regs 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 T_regs 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. 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. 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.