This study was performed to elucidate pathophysiological events prior and during the course of collagen-induced arthritis (CIA) in DA rats. Kinetic studies of local cytokine responses were determined using immunohistochemisrty and computer-aided image analysis. We also investigated the effect of the macrophage-pacifying compound CNI-1493 on proinflammatory cytokine expressions. Synovial cryosections were analysed at various time points for the presence of IL-1β, TNF and TGF-β. Unexpectedly, an early simultaneous TNF and IL-1β expression was detected in resident cells in the lining layer, preceding disease onset by more than one week. The predominant cytokine synthesis by synovial (ED-1+) macrophages coincided with clinical disease. TNF-production greatly exceeded that of IL-1β. CNI-1493 treatment did not affect the early TNF and IL-1β synthesis, while disease-associated TNF and IL-1β production was greatly reduced. Furthermore, CNI-1493 significantly up-regulated synthesis of the anti-inflammatory cytokine TGF-β and thereby shifted the balance of pro-inflammatory and anti-inflammatory cytokines in the arthritic joint in a beneficial way.