IL-1 regulation of transin/stromelysin transcription in rheumatoid synovial fibroblasts appears to involve two antagonistic transduction pathways, an inhibitory, prostaglandin-dependent pathway mediated by cAMP, and a stimulatory, protein kinase C-dependent pathway.
IL-1, like other agents that have been shown a capacity to induce protein kinase C, is a potent transcriptional activator of the metalloproteinase, stromelysin, in synovial and other fibroblasts. cAMP has been shown to inhibit stromelysin transcription in fibroblasts of nonsynovial origin, and is regarded as an important second messenger for IL-1. In addition to stimulating metalloproteinase transcription, IL-1 also induces PGE2 production in synoviocytes. We determined that rIL-1 alpha led to the time-dependent accumulation of intracellular cAMP in serum-starved rheumatoid synovial fibroblasts, and that the effect was blocked by indomethacin. The cAMP agonists forskolin, 3-isobutyl-1-methylxanthine, and PGE2 suppressed the IL-1 induction of stromelysin; conversely, indomethacin superinduced IL-1-elicited stromelysin mRNA. These results were recapitulated on the transcriptional level in cells transfected with the rat transin/stromelysin promoter in a reporter (CAT) construct. 2',5'-Dideoxyadenosine, an inhibitor of adenylate cyclase, also augmented the IL-1 induction of stromeylsin mRNA, as did H-8, a specific inhibitor of the cAMP-dependent protein kinase A. Staurosporine and H-7, inhibitors of protein kinase C, blocked the IL-1 induction of stromelysin mRNA. We conclude that IL-1 appears to stimulate at least two transduction pathways in synovial fibroblasts from patients with rheumatoid arthritis, and that these have antagonistic effects on the regulation of stromelysin transcription.
Case
J P
JP
Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institutes of Health, Bethesda, MD 20892.
Lafyatis
R
R
Kumkumian
G K
GK
Remmers
E F
EF
Wilder
R L
RL
D000067956:Adenylyl Cyclase Inhibitors; D001172:Arthritis, Rheumatoid / Q000378:metabolism; D000242:Cyclic AMP / Q000502:physiology*; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007375:Interleukin-1 / Q000502:physiology*; D019278:Matrix Metalloproteinase 3; D008666:Metalloendopeptidases / Q000235:genetics*; D011453:Prostaglandins / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction; D013583:Synovial Membrane / Q000378:metabolism; D014158:Transcription, Genetic
D000067956:Adenylyl Cyclase Inhibitors; D007375:Interleukin-1; D011453:Prostaglandins; D012333:RNA, Messenger; D000242:Cyclic AMP; D011493:Protein Kinase C; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D007213:Indomethacin