IL-4, a well-recognized modulator of macrophage activation, is perceived as an anti-inflammatory cytokine; however, under certain circumstances IL-4 may function as a proinflammatory cytokine. We have previously demonstrated that IL-4 treatment of mice with proteoglycan-induced arthritis (PGIA) inhibited the development of disease. To determine whether the capacity of IL-4 to inhibit disease is dependent on IL-4-mediated regulation of IL-12, we assessed the requirement for IL-4 in modulating development of PGIA. Immunization of mice, lacking IL-4 and Stat6, with proteoglycan results in a significant increase in arthritis severity in comparison to wild-type controls, suggesting that arthritis severity is regulated by IL-4 through a Stat6-dependent mechanism. Concomitant with exacerbated disease in IL-4−/− mice, there is a significant increase in the systemic production of proinflammatory cytokines IL-12, TNF-α, and IFN-γ and in levels of mRNA transcripts for proinflammatory cytokines and chemokines in joints. Disease is suppressed in Stat4−/− mice indicating that elevated levels of IL-12 contribute to exacerbation of arthritis and that suppression is accompanied by reduced levels of IFN-γ production. In support of this, IFN-γ−/− mice are protected from PGIA and the degree of inflammation is similar to Stat4−/− mice. The decrease in disease severity in IFN-γ−/− and Stat4−/− mice correlates with diminished TNF-α levels but there is no switch to a Th2-type response. Taken together, these results suggest that IL-4 regulates the severity of disease in PGIA by controlling IL-12 production, which in turn regulates the magnitude of IFN-γ expression through a Stat4-dependent pathway.

Background: Proteoglycan aggrecan (PG)-induced arthritis (PGIA) is the only systemic autoimmune murine model which affects the axial skeleton, but no studies have been performed characterising the progression of spine involvement. Objectives: To follow pathological events in experimental spondylitis, and underline its clinical, radiographic, and histological similarities to human ankylosing spondylitis (AS); and to determine whether the spondyloarthropathy is a shared phenomenon with PGIA, or an ''independent'' disease. Methods: Arthritis/spondylitis susceptible BALB/c and resistant DBA/2 mice, and their F1 and F2 hybrids were immunised with cartilage PG, and radiographic and histological studies were performed before onset and weekly during the progression of spondylitis. Results: About 70% of the PG immunised BALB/c mice develop spondyloarthropathy (proteoglycaninduced spondylitis (PGISp), and the progression of the disease is very similar to human AS. It begins with inflammation in the sacroiliac joints and with enthesitis, and then progresses upwards, affecting multiple intervertebral disks. In F2 hybrids of arthritis/spondylitis susceptible BALB/c and resistant DBA/2 mice the incidence of arthritis was 43.5%, whereas the incidence of spondylitis was .60%. Some arthritic F2 hybrid mice had no spondylitis, whereas others developed spondylitis in the absence of peripheral arthritis. Conclusions:The PGISp model provides a valuable tool for studying autoimmune reactions in spondylitis, and identifying genetic loci associated with spondyloarthropathy.

FcγRs are specialized cell surface receptors that coordinately regulate immune responses. Although FcγR expression is a prerequisite for the development of several immune complex-mediated diseases, the mechanism responsible for FcγR-dependent regulation in autoimmunity remains unclear. Therefore, we assessed FcγR-dependent regulation of inflammation in proteoglycan-induced arthritis (PGIA) using FcγR−/− mice. FcγRIIb−/− mice developed arthritis at an earlier time point and with a greater severity than wild-type (WT) mice. In γ-chain−/− (FcγRI−/− and FcγRIII−/−) mice, no clinical or histological evidence of inflammation was observed. Exacerbation of arthritis in FcγRIIb−/− mice correlated with enhanced PG-specific Ab production, but did not significantly affect PG-specific T cell priming. In γ-chain−/− mice, the absence of arthritis did not correlate with serum Ab responses, as PG-specific Ab production was normal. Although PG-specific T cell proliferation was diminished, spleen cells from γ-chain−/− mice successfully adoptively transferred arthritis into SCID mice. Our studies indicated that the mechanism responsible for FcγR regulation of PGIA development was at the level of inflammatory cytokine and β-chemokine expression within the joint. FcγRIIb regulated the development of PGIA by controlling the initiation of cytokine and chemokine expression within the joint before the onset of arthritis, whereas the expression of FcγRI and or FcγRIII controlled cytokine and chemokine expression late in the development of PGIA during the onset of disease. These results suggest that FcγRs are critical for the development of inflammation during PGIA, possibly by maintaining or enhancing inflammatory cytokine and β-chemokine production.