Induction of cyclooxygenase II in human synovial microvessel endothelial cells by interleukin-1. Inhibition by glucocorticoids.
OBJECTIVE
To characterize the effects of interleukin-1 alpha (IL-1) on prostanoid biosynthesis by human rheumatoid synovium microvessel endothelium (HSE).


METHODS
HSE cells were treated with cytokines, metabolic inhibitors, and steroids under various conditions, and prostaglandin biosynthesis was determined by radioimmunoassay. Newly synthesized cyclooxygenase (COX) was quantitated by immunoprecipitation of metabolically labeled HSE cell lysates. The effects of IL-1 on levels of messenger RNA (mRNA) for COX II were also determined.


RESULTS
IL-1 induced an increase in COX activity (as assessed by prostaglandin E2 release) that was dose- and time-dependent and was blocked by cycloheximide, actinomycin D, and dexamethasone. IL-1 induced a selective increase in COX II mRNA and biosynthesis of COX II protein that was blocked by dexamethasone.


CONCLUSIONS
IL-1 treatment of HSE cells induces COX II, as demonstrated by both Northern blotting and immunoprecipitation. The induction of COX II expression provides, at least in part, a mechanism for the pronounced increase in prostanoid synthesis observed in HSE cells following incubation with IL-1. The selective up-regulation of HSE COX II by inflammatory cytokines such as IL-1 suggests that development of specific pharmaceutical inhibitors for this novel isozyme may provide significant new therapeutic advantages in the treatment of RA.
Szczepanski
A
A
Miles Research Center, West Haven Connecticut.
Moatter
T
T
Carley
W W
WW
Gerritsen
M E
ME
D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D008833:Microcirculation; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D013583:Synovial Membrane / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology*; D013997:Time Factors
D016861:Cyclooxygenase Inhibitors; D007375:Interleukin-1; D012333:RNA, Messenger; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone