Type II interleukin-1beta receptor: a candidate for gene therapy in human arthritis.
Interleukin-1 plays a pivotal role in the pathophysiologic process of arthritis. It is released in an autocrine fashion in joints affected with arthritis. Human cartilage affected with arthritis (but not normal cartilage) showed upregulation of interleukin-1beta messenger ribonucleic acid and protein in ex vivo conditions. Type II interleukin-1 receptor, interleukin-1 receptor antagonist, and Type I soluble interleukin-1 receptor has potent interleukin-1 neutralizing activity. In view of these observations, the role of type II interleukin-1 receptor in chondrocyte function was examined. Human interleukin-1beta (5-10 ng/mL) induced nitric oxide, prostaglandin E2 and matrix metalloprotease production in bovine or human chondrocytes, which could be inhibited by 500 pg/mL of Type II interleukin-1 receptor. Interleukin-1 inhibited proteoglycan synthesis that could be reversed by Type II soluble interleukin-1 receptor. Similarly, 1 ng/mL human interleukin-1 induced (or spontaneously produced) nitric oxide and prostaglandin E2 production in human osteoarthritis-affected cartilage could be inhibited by 50% or greater with 100 pg/mL Type II interleukin-1 receptor in ex vivo conditions. Type II interleukin-1 receptor transfected chondrocytes were immune to the insults of exogenous interleukin-1. These experiments showed that endogenous or exogenous Type II interleukin-1 receptor can attenuate the effects of interleukin-1 with respect to induction of inflammatory mediators, matrix metalloprotease activity and, proteoglycan synthesis in human chondrocytes and cartilage.
Amin
A R
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Department of Rheumatology, Hospital for Joint Diseases, New York, NY 10003, USA.
D000818:Animals; D002358:Cartilage, Articular / Q000378:metabolism*; D002417:Cattle; D019902:Chondrocytes / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis; D015316:Genetic Therapy; D006801:Humans; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D010003:Osteoarthritis / Q000378:metabolism / Q000628:therapy*; D011509:Proteoglycans / Q000096:biosynthesis; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology; D053574:Receptors, Interleukin-1 Type II; D014162:Transfection
D007375:Interleukin-1; D011509:Proteoglycans; D017472:Receptors, Interleukin-1; D053574:Receptors, Interleukin-1 Type II; D009569:Nitric Oxide; D020782:Matrix Metalloproteinases; D015232:Dinoprostone