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IL-4 and IL-12 Regulate Proteoglycan-Induced Arthritis Through Stat-Dependent Mechanisms¹

Alison Finnegan^2,*,, Michael J. Grusby, Charles D. Kaplan, Shannon K. O’Neill, Hermann Eibel^¶, Tamas Koreny, Matyas Czipri, Katalin Mikecz^*,, and Jian Zhang^,

^* Section of Rheumatology, Department of Medicine, and Departments of Immunology/Microbiology and Orthopedic Surgery and Biochemistry, Rush Presbyterian-St. Luke’s Medical Center, Chicago, IL 60612; Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115; and ^¶ Klinische Forschergruppe fur Rheumatologie, Freiburg, Germany

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-, and IFN- 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- production. In support of this, IFN-^-/- mice are protected from PGIA and the degree of inflammation is similar to Stat4^-/- mice. The decrease in disease severity in IFN-^-/- and Stat4^-/- mice correlates with diminished TNF- 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- expression through a Stat4-dependent pathway.

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