MAJOR ROLE FOR INTERLEUKIN-1 BUT NOT FOR TUMOR-NECROSIS-FACTOR IN EARLY CARTILAGE DAMAGE IN IMMUNE-COMPLEX ARTHRITIS IN MICE

Objective. To determine the regulating role of interleukin-1 alpha and beta (IL-1 alpha,beta) and tumor necrosis factor alpha (TNF-alpha) in hibition of proteoglycan synthesis and proteoglycan degradation in ear ly immune complex arthritis (ICA) in the mouse. Methods. In the early phases of arthritis, IL-1 and TNF were measured using cytokine specifi c bioassays, the NOB.1 EL-4 and L929 assay, respectively, The impact o f IL-1 in proteoglycan synthesis was studied by neutralizing the forme d IL-1 during early arthritis either by giving anti-IL-1 specific anti bodies intravenously or IL-1 receptor antagonist (IL-1ra) intraperiton eally by osmotic pumps. TNF-alpha was neutralized by giving monoclonal antibodies directed against murine TNF-alpha. Synthesis of proteoglyc ans was measured ex vivo by uptake of S-35-sulfate by patellae derived from inflamed and control, noninflamed knee joints. In vivo formation of S-35-sulfate labeled proteoglycans was studied by autoradiography. Degradation of proteoglycans was measured by labeling patellae in viv o with S-35-sulfate before arthritis induction. Results. High levels o f IL-1 are formed during the first phase of immune complex arthritis ( ICA), Neutralization of either IL-1 alpha or R with specific polyclona l antibodies resulted only in partial blocking, whereas a combination fully blocked inhibition of proteoglycan synthesis. Full blocking was also found after systemic treatment with high amounts of IL-1 receptor antagonist (1.2 mg/day during 3 days). Influx of cells was also signi ficantly reduced both in the anti-IL-1 as well as in the IL-1ra treate d groups, Whether infiltrating cells are involved in inhibition of pro teoglycan synthesis was further investigated in neutropenic mice, Sign ificantly higher levels of IL-1 were found in arthritic joints of neut ropenic compared with control mice, Suppression of proteoglycan synthe sis was similar in arthritic knee joints of normal and neutropenic mic e. However, only minor proteoglycan degradation was found in the latte r. TNF-alpha was undetectable in the bioassay in early ICA and neutral ization of TNF-alpha did not change either swelling, cell influx, prot eoglycan synthesis or proteoglycan degradation. Conclusion. Local prod uction of IL-1 in ICA in knee joints seems directly responsible for in hibition of proteoglycan synthesis. A direct role of IL-1 in proteogly can loss is unlikely, but indirectly IL-1 may be involved in proteogly can breakdown by attracting inflammatory Icukocytes and activating syn ovial cells, TNF-alpha seemed to have no effect on either cell influx, proteoglycan synthesis or proteoglycan degradation in this model.