Dynamics of early synovial cytokine expression in rodent collagen-induced arthritis - A therapeutic study using a macrophage-deactivating compound

This study was performed to elucidate pathophysiological events before and during the course of collagen-induced arthritis in Dark Agouti rats, a mode l for rheumatoid arthritis, Kinetic studies of local cytokine responses wer e determined using immunohistochemical techniques, quantified by computer-a ssisted image analysis. We recently reported that the macrophage-pacifying agent CNI-1493 successfully ameliorated collagen-induced arthritis. In the present trial, we investigated the potential of CMI-1493 to down-regulate p ro-inflammatory cytokines, Synovial cryosections were analyzed at various t ime points for the presence of interleukin (IL)-1 beta, tumor necrosis fact or (TNF), and transforming growth factor (TGF)-beta, Unexpectedly, an early simultaneous TNF and IL-1 beta expression was detected in resident cells i n the Lining layer, preceding disease onset and inflammatory cell infiltrat ion by >1 week. The predominant cytokine synthesis by synovial (ED1(+)) mac rophages coincided with clinical disease. TNF production greatly exceeded t hat of IL-1 beta. CNI-1493 treatment did not affect the early disease-prece ding TNF and IL-1 beta synthesis in the lining layer. However, after diseas e onset, CNI-1493 intervention resulted in a pronounced reduced IL-1 beta a nd in particular TNF expression. Furthermore, CNI-1493 significantly up-reg ulated synthesis of the anti-inflammatory cytokine TGF-P and thereby shifte d the balance of pro-inflammatory and anti-inflammatory cytokines in the ar thritic joint in a beneficial way.