3.3. Multidirectional Function of IL-6 in RA Pathogenesis

IL-6 is involved in a wide range of physiological processes, such as the immune response, inflammation, and bone metabolism, and has also been implicated in the pathogenesis of RA [1,17,55]. Here, we describe recent advances in knowledge regarding the regulation of Treg and Tfh cells, osteoclastogenesis, and VEGF production.

IL-6 regulates the differentiation of Treg, Th17, and Tfh cells. The IL-6-STAT3 pathway is required for Th17 cell development, and enhancement of the IL-6-STAT3 signaling axis causes IL-17A-dependent autoimmune arthritis in mice [62]. The importance of STAT3 in the differentiation of Th17 cells has also been demonstrated in humans [63]. Furthermore, IL-6 downregulates Foxp3 expression through STAT3 and induces the genetic reprogramming of Treg cells to Th17-like cells [64]. Thus, IL-6 regulates the Treg vs. Th17 cell balance. Conversion of Treg cells to Th17 cells is induced by IL-6 derived from synovial fibroblasts, and the converted Th17 cells are more osteoclastogenic than conventional Th17 cells [65].

T follicular helper (Tfh) cells have been identified as CXCR5+ PD-1+ CD4+ T cells, which regulate the differentiation of B cells into plasma cells and memory B cells by mediating class switching and affinity maturation of antibodies in germinal centers [66]. In mice, Bcl6+CXCR5+ Tfh differentiation is severely impaired in the absence of IL-6, suggesting that IL-6 is an essential factor for the development of murine Tfh cells [67]. In humans, however, Tfh differentiation might be less affected by IL-6, and TGF-β together with IL-12 or IL-23 induces various Tfh markers on CD4+ T cells [68].

IL-6 also regulates osteoclastogenesis in combination with TNF. Extensive analysis of osteoclast differentiation has identified various osteoclast types. Osteoclasts regulate bone absorption and bone mineral density (BMD), and cause bone erosion in both RA patients and model mice [22]. Differentiation of osteoclasts depends on TNF and RANKL, IL-6, and IL-17.

IL-6 also upregulates the expression of VEGF, which is also a pivotal cytokine in RA development [69]. Joint inflammation in RA is associated with angiogenesis, and migration of immune cells into the joint contributes to the pathogenesis of RA [70]. Although early administration of anti-VEGF antibody was reported to ameliorate vascularization and joint swelling in a CIA model mouse, later administration was not effective. These results suggest that angiogenesis via VEGF contributes to the early stage of RA pathogenesis. The synergistic effect of IL-6, IL-1β, and TNF on VEGF production is only impaired by anti-IL-6R antibody, but not by blockade of TNF or IL-1β, indicating that IL-6 is one of the major players in VEGF induction [71].

3.4. Evaluation of Anti-IL-6 Agents

IL-6 is involved in a wide range of physiological processes, such as the immune response, inflammation, and bone metabolism, and has also been implicated in the pathogenesis of RA. Anti-IL-6 receptor antibody was first approved for RA in 2008, and high efficacy in the treatment of RA has been demonstrated [48,49,50,51,52,55]. Due to the wide range of concentration of IL-6 in RA patients, clinical application of anti-IL-6 antibody seems to be difficult. In fact, clinical trials of the anti-IL-6 antibody sirukumab for RA were not successful [72]. The Food and Drug Administration (FDA) have declined the approval of this agent because of a trend for increased overall mortality with sirukumab vs. placebo. The mortality was mainly associated with cardiovascular events, infection, and malignancy. IL-6 activates the JAK-STAT system, and JAK inhibitors have a remarkable effect on RA [1,17,48,49,50,51,52]. Various cytokines regulate a number of downstream signaling molecules in RA, and these are potential therapeutic targets [10]. However, inhibition of pathways other than the JAK-STAT system is not considered to be easy due to the problem of crosstalk in which signals enter from other pathways.