Interleukin 35 (IL-35) is a recently discovered anti-inflammatory cytokine from theIL-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 is a dimeric protein composed ofIL-12α andIL-27β chains, which are encoded by two separategenes calledIL12A andEBI3 (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 toIL-12 p40 and to the ciliary neurotrophic factor receptor, whose expression is induced in B lymphoblastoid cells byEBV infection[7]
Secreted by regulatory T-cells (Tregs), regulatory B-cells (Bregs)[8] or even CD8+ regulatory T cells,[9] IL-35 suppressesinflammatory 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 inducesproliferation of Treg cell populations but reduces activity ofTh17 cell populations.[12]
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 duringcell culture experiments and using an experimental model forinflammatory 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 asVEGF 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 ofEAE 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 microbeSalmonella 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 andBregs is much higher than T1D patients with no remaining C-peptide.[18]
It has been shown that IL-35 increases replication of HBV virus both in vitro and in transgenic mice by targeting its transcription factorHNF4α.[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 likegastric cancer through influencing Tregs function and the secretion of immunomodulatory cytokines such asIL-10,IL-35, andTGF-β.[24]
^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.PMID17874423.S2CID38306559.
^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.PMID26922678.
^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.PMID28850026.
