Cytokine mRNA in the joints and draining lymph nodes of rats with adjuvant arthritis and effects of cyclosporin A.
TNF-alpha and IL-1beta promote leukocyte recruitment to arthritic joints and may contribute to cartilage degradation while regulatory cytokines such as IL-4 and IL-1RA may in part determine the course of arthritis. Here we report the pattern of TNF-alpha, IL-1beta, IL-6, IFN-gamma, IL-1RA, and IL-4 mRNA expression, detected by RT/PCR, in the talar joint and draining popliteal lymph node (PLN) of rats with adjuvant arthritis (AA). Levels of TNF-alpha and IFN-gamma mRNA were increased in the PLN before clinical signs of arthritis. This was followed by increases in IL-1beta and IL-1RA mRNA at d9 and IL-6 mRNA at d12. PLN IL-1RA mRNA levels were positively correlated with those of IL-1beta and TNF-alpha throughout d5-d20. IL-4 mRNA levels were highest on days 7 and 20. In the synovium, a small increase in TNF-alpha, IL-1beta, and IL-6 mRNA was detected on d5 then again on d12. Maximal synovial TNF-alpha levels were reached on d20, while IL-1beta peak expression was on d16 and IL-6 on d14. IL-4, IL-1RA, and IFN-gamma mRNA was undetectable in the synovium. Cyclosporin treatment for 4 days, initiated at the height of arthritis, rapidly decreased clinical disease, and decreased migration of neutrophils and T lymphocytes into the joints. Yet no significant effect of CyA was observed on inflammatory cytokine expression, although the correlation between PLN IL-1RA and IL-1beta or TNF-alpha was lost in treated animals. Thus there is a variable pattern of cytokine gene expression in rat AA, the undetectable IL-4 and IFN-gamma mRNA in synovium being analogous to human rheumatoid arthritis.
Department of Pediatrics, Dalhousie University, Halifax, NS, Canada.
L M
LM
Ayer
A C
AC
Issekutz
C C
CC
Waterhouse
A W
AW
Stadnyk
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology* / Q000627:therapeutic use; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D008198:Lymph Nodes / Q000378:metabolism*; D008297:Male; D023421:Models, Animal; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012795:Sialoglycoproteins / Q000096:biosynthesis / Q000235:genetics; D013583:Synovial Membrane / Q000378:metabolism*; D013643:Tarsus, Animal / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D016207:Cytokines; C507763:IL1RN protein, human; D007166:Immunosuppressive Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015850:Interleukin-6; D012333:RNA, Messenger; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007371:Interferon-gamma; D016572:Cyclosporine