Induction of cyclooxygenase-2 is responsible for interleukin-1 beta-dependent prostaglandin E2 synthesis by human lung fibroblasts.
Because interleukin-1 beta (IL-1 beta) increases the synthesis of prostaglandin E2 (PGE2) in human lung fibroblasts, the effect of IL-1 beta on the expression of two isozymes of cyclooxygenase (cyclooxygenase-1 and -2) in human embryonic lung fibroblasts (IMR-90) was investigated in terms of three parameters (PGE2 release, cyclooxygenase activity, and mRNA). When the cells were incubated with IL-1 beta, both the PGE2 release to the culture medium and the cyclooxygenase activity in the cell lysate increased in a dose- and time-dependent manner, and both were inhibited by NS-398 (a cyclooxygenase-2-specific inhibitor). Dexamethasone and interleukin-4 (IL-4) inhibited the IL-1 beta-induced PGE2 synthesis; the former inhibited the IL-1 beta-induced cyclooxygenase activity whereas the latter failed. As analyzed by Northern blot, cyclooxygenase-1 mRNAs (3.0 Kb and 5.0 Kb) were detected with resting cells and did not increase by the addition of IL-1 beta. In contrast, the cyclooxygenase-2 mRNA (4.4 Kb) was undetectable with resting cells, but was increased dramatically up to 4 to 8 h by the addition of IL-1 beta. Dexamethasone inhibited the IL-1 beta-induced mRNA expression of cyclooxygenase-2 whereas IL-4 failed. These results indicate that IL-1 beta induces cyclooxygenase-2 rather than cyclooxygenase-1 in IMR-90 cells and this induction is responsible for the augmentation of PGE2 production stimulated with IL-1 beta. However, the inhibition of the IL-1 beta-induced PGE2 synthesis by IL-4 was not mediated by the down-regulation of cyclooxygenase-2.
Endo
T
T
Third Department of Internal Medicine, School of Medicine, Tokushima University, Japan.
Ogushi
F
F
Sone
S
S
Ogura
T
T
Taketani
Y
Y
Hayashi
Y
Y
Ueda
N
N
Yamamoto
S
S
D001483:Base Sequence; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D017931:DNA Primers / Q000737:chemistry; D003609:Dactinomycin / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D005347:Fibroblasts; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology; D008168:Lung / Q000378:metabolism*; D008969:Molecular Sequence Data; D009578:Nitrobenzenes / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology
D017931:DNA Primers; D007375:Interleukin-1; D009578:Nitrobenzenes; D012333:RNA, Messenger; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D003609:Dactinomycin; D015847:Interleukin-4; D003907:Dexamethasone; D003513:Cycloheximide; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D007213:Indomethacin