Interleukin-18 Acts as a Proinflammatory Stimulus in Rheumatoid Arthritis

Functionally distinct T-cell subsets, known as Th1 and Th2, are recognized. In rheumatoid arthritis (RA), there is T-cell polarization in which Th1 cells predominate and are thought to drive the inflammatory response. It is unclear what initiates and sustains the Th1 response, however, one potential explanation is over expression of interleukin-18 (IL-18). IL-18 exhibits synergy with IL-12 in promoting Th1 responses, induces proliferation, upregulates IL-2R a expression, and promotes TNF-a, and GM-CSF production by Th1 clones. Gracie, et al (J Clin Invest 104:1393-1401, 1999) examined the role of IL-18 in promoting rheumatoid synovitis.

Using RT-PCR significantly higher levels of IL-18 mRNA and protein were detected in the synovial tissues of rheumatoid arthritis (RA) patients as compared to those from osteoarthritis (OA) controls. To determine distribution, synovia were stained with a mAB to human IL-18. Lymphocytic aggregates stained most prominently for IL-18 expression, primarily residing in CD 68+ macrophages. A small number of CD68-, IL-18+ cells were also detected, most likely fibroblasts. No staining for IL-18 was detected in CD3+ lymphocytes. IL-18 receptor (IL-18R) mRNA was also detected in 10 of 10 RA synovial membrane. Using FACS analysis, IL-18R expression was detected in significant subpopulations of CD3+ synovial fluid lymphocytes and CD14+ macrophages. Cytokine production was also determined. IL-18, together with IL-12 or IL-15 induced significant production of INF-gin synovial tissues in vitro and alone, promoted GM-CSF and nitric oxide production. Using the murine collagen-induced arthritis (CIA) model, mice developed high incidence and severity of arthritis when IL-18 was coadministered with CII/IFA priming and challenge when compared to controls that received CII/IFA alone.

These data confirm that IL-18 promotes articular Th1 responses but may also act directly on macrophages to induce proinflammatory cytokine production. That these effects may have pathophysiological significance in RA is indicated by the ability of IL-18 to promote collagen-induced arthritis in mice.