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 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)-1beta, tumor necrosis factor (TNF), and transforming growth factor (TGF)-beta. Unexpectedly, an early simultaneous TNF and IL-1beta 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-1beta. CNI-1493 treatment did not affect the early disease-preceding TNF and IL-1beta synthesis in the lining layer. However, after disease onset, CNI-1493 intervention resulted in a pronounced reduced IL-1beta 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.
Palmblad
K
K
Department of Rheumatology, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden. karin.palmblad@cmm.ki.se
Erlandsson-Harris
H
H
Tracey
K J
KJ
Andersson
U
U
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001168:Arthritis / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D003094:Collagen / Q000008:administration & dosage*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000187:drug effects; D006835:Hydrazones / Q000627:therapeutic use; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013583:Synovial Membrane / Q000737:chemistry* / Q000166:cytology / Q000187:drug effects; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000813:Anilides; D006146:Guanidines
D000894:Anti-Inflammatory Agents, Non-Steroidal; D003094:Collagen; D016207:Cytokines; D006835:Hydrazones; D007375:Interleukin-1; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C097256:semapimod; D000813:Anilides; D006146:Guanidines