Pathogenesis and Function of Interleukin-35 in Rheumatoid Arthritis

Abstract

It is well known that RA (Rheumatoid arthritis) is an autoimmune disease characterized by multiple and symmetric arthropathy. The main pathological features of RA are synovial hyperplasia, angiogenesis, pannus formation, inflammatory cell infiltration, articular cartilage, bone destruction, and ultimately joint dysfunction, even deformity. IL-35 (Interleukin-35) is a new member of the IL-12 (Interleukin-12) family, which is an immunosuppressive and anti-inflammatory cytokine secreted mainly by Treg (T regulatory cells). There is evidence suggested that IL-35 can attenuate the progression of RA through influencing the immune and pathological process. It suggests that IL-35 played an important role in the pathogenesis of RA, and can be used as a potential target for the future treatment of RA. This review summarizes the recent advances of IL-35 in the pathological roles and the therapeutic potential roles in RA.

Keywords: IL-12 family; IL-35; Th17; article highlights; rheumatoid arthritis; treg.

FIGURE 1

The structure of IL-12 family. IL-12 family is composed of A chains (p19, p28, or p35) and B chains (p40 or Ebi3). P40 can be paired with p35 or p19 to form IL-12 or IL-23. Respectively, while Ebi3 can pair with p28 or p35 to form IL-27 or IL-35. IL-12 receptor is composed of IL-12R β2 and IL-12R β1. IL-23 receptor is composed of IL-12R β1 and IL-23R. IL-27 receptor is composed of WSX-1and gp-130. IL-35 receptor is composed of IL-12R β2 and gp-130.

FIGURE 2

A schematic model for the immune pathway of IL-35 in RA. Th1, Th2, Th17, and Treg are all differentiated from the Th Cells, which can differentiate into different cell subsets under the influence of different cytokines and transcription factors. As shown in the figure, IL-35 stimulates the differentiation of Th cells into Treg and iTR35. IL-10 and TGF-β are secreted by Treg, and IL-35 inhibits the differentiation of Th cells into other helper T cells, especially Th17. IL-35 also acts on DCs and macrophages to inhibit inflammation.

FIGURE 3

The regulatory mechanism of IL- 35 in RA. IL-35 is secreted by Treg via JAK/STAT signaling pathway. Production of IL-35 and IL-10 triggers Th17 differentiation. In turn, IL-35 which produced by Treg cells, enhances IL-35 expression. Moreover, IL-35 also inhibits Ang2/Tie2 via NF-κB, and with the suppression of VEGF, VEGFR, Tie2, it causes angiogenesis. IL-35 also stimulates OPG secretion and competitively binded RANKL with OPG by inhibiting Wnt/β-catenin signaling pathway, and it inhibits bone destruction in the course of RA. Thus, IL-35 acts as an anti-inflammatory factor participating in RA via various pathways.

FIGURE 4

Gut microbiota in RA. The human gut microbiota has a critical role in the pathogenesis of RA. By an interdependent functional relationship, the composition and functions of the gut microbiota plays a role in regulating the Th17/Treg cells balance and affected the host immune responses. Bacteroides fragilis as a normal symbiotic bacterium in the human gut, it mediates the conversion of CD4⁺ T cells to interleukin (IL)-10 through a specific molecule, polysaccharide a (PSA), to produce Foxp3+ Treg cells. While Segmented filamentous bacterium (SFB), commensal, is found inducing and activating of Th17 cells in the lamina propria, which subsequently secreted pro-inflammatory cytokine (IL-17), and enhanced mucosal immune responses of the host.