The roles of interleukin-6 in the pathogenesis of rheumatoid arthritis

Abstract

Several clinical studies have demonstrated that the humanized anti-interleukin-6 (IL-6) receptor antibody tocilizumab (TCZ) improves clinical symptoms and prevents progression of joint destruction in rheumatoid arthritis (RA). However, the precise mechanism by which IL-6 blockade leads to the improvement of RA is not well understood. IL-6 promotes synovitis by inducing neovascularization, infiltration of inflammatory cells, and synovial hyperplasia. IL-6 causes bone resorption by inducing osteoclast formation via the induction of RANKL in synovial cells, and cartilage degeneration by producing matrix metalloproteinases (MMPs) in synovial cells and chondrocytes. Moreover, IL-6 is involved in autoimmunity by altering the balance between T(h)17 cells and T(reg). IL-6 also acts on changing lipid concentrations in blood and on inducing the production of hepcidin which causes iron-deficient anemia. In conclusion, IL-6 is a major player in the pathogenesis of RA, and current evidence indicates that the blockade of IL-6 is a beneficial therapy for RA patients.

Figure 1

IL-6 signaling.

Figure 2

Mechanism of RANKL induction by cytokines.

Figure 3

Hepcidin mRNA induction by arthritic serum in Hep3B cells [7]. Hep3B cells were incubated with serum from healthy, arthritic, or tocilizumab-treated monkeys for 24 h. Tocilizumab was added simultaneously with serum. After incubation, total mRNA was extracted, and hepcidin mRNA was measured by real-time PCR. The hepcidin expression induced by medium alone (without serum) was defined as 1. Each point represents the mean and SD of 3 monkeys. Statistical significances between healthy animals and arthritic animals and between control and the addition of tocilizumab were analyzed by unpaired t-test. *P < .05 (healthy animals' serum, control versus arthritic animals' serum, control), ^† P < .05 (arthritic animals' serum, control versus arthritic animals' serum, tocilizumab).

Figure 4

Serum lipid levels in IL-6-treated mice [8]. (a) Experimental protocol. Mice (n = 6) were given i.p. IL-6 (20 μg) or phosphate buffered saline (PBS) twice a day 5 days per week for 2 weeks. (b) Serum total cholesterol and triglyceride levels were measured with an automatic analyzer. Closed and open circles indicate control and IL-6-treated mice, respectively. The horizontal bar indicates mean of values. Statistical significance between the control and the IL-6 group on days 0, 7, and 14 was analyzed by unpaired t-test (***P < .05).

Figure 5

Mode of action of tocilizumab.