Interleukin‐35 in immune‐related diseases: protection or destruction

Abstract

Summary Interleukin‐35 (IL‐35) is a recently identified heterodimeric cytokine in the IL‐12 family. It consists of an IL‐12 subunit α chain (P35) and IL‐27 subunit Epstein–Barr virus‐induced gene 3 (EBI3) β chain. Unlike the other IL‐12 family members, it signals through four unconventional receptors: IL‐12Rβ2–IL‐27Rα, IL‐12Rβ2–IL‐12Rβ2, IL‐12Rβ2–GP130, and GP130–GP130. Interleukin‐35 signaling is mainly carried out through the signal transducer and activator of transcription family of proteins. It is secreted not only by regulatory T (Treg) cells, but also by CD8+ Treg cells, activated dendritic cells and regulatory B cells. It exhibits immunosuppressive functions distinct from those of other members of the IL‐12 family; these are mediated primarily by the inhibition of T helper type 17 cell differentiation and promotion of Treg cell proliferation. Interleukin‐35 plays a critical role in several immune‐associated diseases, such as autoimmune diseases and viral and bacterial infections, as well as in tumors. In this review, we summarize the structure and function of IL‐35, describe its role in immune‐related disorders, and discuss the mechanisms by which it regulates the development and progression of diseases, including inflammatory bowel disease, collagen‐induced arthritis, allergic airway disease, hepatitis, and tumors. The recent research on IL‐35, combined with improved techniques of studying receptors and signal transduction pathways, allows for consideration of IL‐35 as a novel immunotherapy target.

Increased Interleukin-35 suppresses peripheral CD14+ monocytes function in patients with Kawasaki disease

“…To the best of our knowledge, this was the first study on the direct regulatory role of IL-35 to CD14 + monocytes in Kawasaki disease. We showed an elevation of plasma IL- 35 Recent studies have revealed abnormal expression of IL-35 in inflammatory autoimmune diseases, and suggested the critical regulatory role in the onset and development of these diseases [21,22]. Decreased expression of peripheral IL-35 was reported in patients with systemic lupus erythematosus [23], multiple sclerosis [24], primary Sjogren's syndrome [25], and psoriasis vulgaris [26].…”

In Vitro Characterization of Gut Microbiota-Derived Commensal Strains: Selection of Parabacteroides distasonis Strains Alleviating TNBS-Induced Colitis in Mice

“…Indeed, we were able to show that PF-BaE5 and PF-BaE7-primed DCs promoted the polarization of CD4 + T cells towards a regulatory phenotype (CD4 + FoxP3 + IL-10 + ) with an increased expression of the gene encoding Ebi3. Ebi3 is a subunit of the heterodimeric cytokine IL-35, a potent immunosuppressive cytokine secreted by Tregs and B regulatory cells with a strong ability to inhibit T cell differentiation and effector functions [ 76 ]. IL-35-induced Treg cells (iTr35) produce more IL-35 [ 77 ] and type 1 Treg cells (Tr1) use IL-35 to suppress the immune response [ 78 ].…”

Future prospects for CD8+ regulatory T cells in immune tolerance

“…66,72 Although IFNγ has proinflammatory consequences it has also been described as having pro-tolerogenic actions, through the production of molecules such as IDO, iNOs and FGL2. 66,72 Although IFNγ has proinflammatory consequences it has also been described as having pro-tolerogenic actions, through the production of molecules such as IDO, iNOs and FGL2.…”

“…IL-35 has been previously described as expressed by CD4 + Tregs 71 but it has also been described as expressed and playing a suppressive role for tumor-associated CD8 + Tregs. 66,72 Although IFNγ has proinflammatory consequences it has also been described as having pro-tolerogenic actions, through the production of molecules such as IDO, iNOs and FGL2. 68 IFNγ has been described as produced by several CD8 + Treg types 3,4,65,[73][74][75][76][77] although the function of IFNγ in CD8 + FOXP3 + cells has not been specifically analyzed.…”