Preincubation of human synovial cells with IL-1 modulates prostaglandin E2 release in response to bradykinin.
Kinins are vasoactive peptides whose potent inflammatory and bone resorbing properties suggest a role for these autacoids in the pathogenesis of inflammatory arthritis. We used cultured human synovial cells as a model to evaluate the effects of bradykinin on articular tissue. In resting synovial cells, bradykinin was a relatively ineffective stimulus for PGE2 production. However, after a period of preincubation with the cytokine, IL-1, which is itself a stimulus for PGE2 production, synovial cells exhibited a further striking time- and dose-dependent response to bradykinin. Maximal release of PGE2 was observed in response to 10(-7) to 10(-6) M bradykinin after first pretreating the cells for 24 h with 5 to 10 U/ml of IL-1. rIL-1 alpha and IL-1 beta, as well as rTNF-alpha, induced a similar response to bradykinin in synovial cells, whereas recombinant IL-2 did not. The bradykinin analog, lysylbradykinin, was equipotent in inducing PGE2 release from IL-1 pretreated synovial cells, whereas des(Arg9) bradykinin, substance P, and neurokinins A and B were ineffective in this regard in both IL-1-pretreated and in resting cells. Synovial cells derived from patients with rheumatoid arthritis and osteoarthritis responded similarly to bradykinin. The synergistic response in PGE2 production induced by IL-1 and bradykinin was significantly inhibited by pretreatment with 1 microM indomethacin or dexamethasone (96 and 94% inhibition, respectively). In addition, the response was abrogated by pretreatment with 10 micrograms/ml of cycloheximide or actinomycin D (81 and 97% inhibition, respectively). These data provide the first description of synergism of IL-1 with a noncytokine peptide in human synovial cells. The ability of IL-1 to increase the responsiveness of synovial tissues to bradykinin may play an important role in potentiating inflammatory responses within the joint.
Bathon
J M
JM
Johns Hopkins University School of Medicine, Department of Medicine, Baltimore, MD.
Proud
D
D
Krackow
K
K
Wigley
F M
FM
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D001920:Bradykinin / Q000378:metabolism / Q000494:pharmacology*; D000001:Calcimycin / Q000494:pharmacology; D002478:Cells, Cultured; D015237:Dinoprost / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D007700:Kinetics; D015288:Neurokinin A / Q000494:pharmacology; D013373:Substance P / Q000494:pharmacology; D013583:Synovial Membrane / Q000276:immunology* / Q000378:metabolism
D000276:Adjuvants, Immunologic; D007375:Interleukin-1; D013373:Substance P; D000001:Calcimycin; D015288:Neurokinin A; D015237:Dinoprost; D015232:Dinoprostone; D001920:Bradykinin