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Regular Article |
From the Department of Rheumatology,*
Center for
Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; the
Department of Rheumatology,
Astrid Lindgren’s
Children’s Hospital, Karolinska Hospital, Stockholm, Sweden; and the
Laboratory of Biomedical Science,
North Shore
University Hospital, Manhasset, New York
This study was performed to elucidate pathophysiological events before and during the course of collagen-induced arthritis in Dark Agouti rats, a model for rheumatoid arthritis. Kinetic studies of local cytokine responses were determined using immunohistochemical techniques, quantified by computer-assisted 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 CNI-1493 to down-regulate pro-inflammatory cytokines. Synovial cryosections were analyzed at various time points for the presence of interleukin (IL)-1{beta}, tumor necrosis factor (TNF), and transforming growth factor (TGF)-{beta}. Unexpectedly, an early simultaneous TNF and IL-1{beta} expression was detected in resident cells in the lining layer, preceding disease onset and inflammatory cell infiltration by >1 week. The predominant cytokine synthesis by synovial (ED1+) macrophages coincided with clinical disease. TNF production greatly exceeded that of IL-1{beta}. CNI-1493 treatment did not affect the early disease-preceding TNF and IL-1{beta} synthesis in the lining layer. However, after disease onset, CNI-1493 intervention resulted in a pronounced reduced IL-1{beta} and in particular TNF expression. Furthermore, CNI-1493 significantly up-regulated synthesis of the anti-inflammatory cytokine TGF-{beta} and thereby shifted the balance of pro-inflammatory and anti-inflammatory cytokines in the arthritic joint in a beneficial way.
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