Inflammatory cytokine levels in paw tissues during development of rat collagen-induced arthritis: effect of FK506, an inhibitor of T cell activation.
OBJECTIVE
To characterize rat collagen-induced arthritis (CIA) on the basis of levels of inflammatory cytokines, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6 in paw tissues, and further investigate the effect of FK506 (tacrolimus), a potent inhibitor of T cell activation, on cytokine levels.


METHODS
CIA was induced in female Lewis rats. The volume of hindpaws was measured before and after collagen immunization. TNF-alpha, IL-1beta and IL-6 levels in paw tissue extracts were determined by ELISA. Proteoglycan contents of cartilage in femoral heads was measured as an indication of cartilage destruction. To assess the effect of FK506 on inflammatory cytokine levels, rats were orally treated with 5 mg/kg of FK506 from days 14-21.


RESULTS
TNF-alpha a level in paw tissues did not significantly change compared to levels found before collagen immunization, throughout development of CIA. In contrast, IL-1beta and IL-6 levels in paw tissues significantly increased between day 14 and day 28 after collagen imuninization, when the arthritis was at a developed stage. Therapeutic treatment with FK506 reduced the elevated level of IL-6, but not IL-1beta, in paw tissue. FK506 treatment was effective in suppressing paw swelling and also recovering the loss of proteoglycan contents in the cartilage.


CONCLUSIONS
Levels of IL-1beta and IL-6, but not TNF-alpha , in paw tissue were upregulated in association with the development of arthritis in rat CIA. These results suggest that IL-1beta and IL-6, rather than TNF-alpha , may play important roles at local inflammatory sites in producing joint destruction in rat CIA. FK506 may improve arthritis in established stages of CIA, by reducing the elevated level of IL-6.
Magari
K
K
Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6, Kashima, 532-8514 Yodogawa-ku, Osaka, Japan.
Miyata
S
S
Ohkubo
Y
Y
Mutoh
S
S
D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology*; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology*; D003094:Collagen / Q000008:administration & dosage*; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects; D005260:Female; D006614:Hindlimb / Q000473:pathology / Q000503:physiopathology; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D007375:Interleukin-1 / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000096:biosynthesis*; D051381:Rats; D011917:Rats, Inbred Lew; D016559:Tacrolimus / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome; D015854:Up-Regulation
D016207:Cytokines; D007166:Immunosuppressive Agents; D007375:Interleukin-1; D015850:Interleukin-6; D003094:Collagen; D016559:Tacrolimus