Inhibition by corticosteroids of epidermal growth factor-induced recovery of cyclooxygenase after aspirin inactivation.
Cultures of vascular smooth muscle cells superfused with [14C]arachidonic acid synthesized the antiplatelet substance prostacyclin as the major cyclooxygenase product. Prostacyclin synthesis was inactivated by aspirin, which irreversibly acetylates cyclooxygenase. Aspirin-treated cells recovered within 2 h by a process that was blocked by cycloheximide but not by actinomycin D, and that required a serum component identified as epidermal growth factor (EGF). EGF-induced recovery of cyclooxygenase was greatly potentiated by type beta transforming growth factor (TGF-beta). Incubation with EGF and TGF-beta in the 0.1-1.0 nanomolar range stimulated cyclooxygenase recovery up to 20-fold without increasing [35S]methionine incorporation into other cell proteins. Induction of cyclooxygenase by EGF and TGF-beta also was prevented by cycloheximide but not by actinomycin D. EGF-dependent recovery was blocked by preincubation with dexamethasone (2 microM), an effect that was duplicated by pure lipocortin (2-4 micrograms/ml). Incubation of membrane preparations from these cells with EGF selectively activated phosphorylation of a 35-kDa cellular protein that comigrated with lipocortin. The results suggest that cyclooxygenase recovery in aspirin-inactivated vascular smooth muscle cells is mediated by an EGF-dependent translational control that is inhibited by corticosteroids. The findings also provide a new mechanism whereby corticosteroids suppress inflammatory prostaglandins.
Pash
J M
JM
Biochemistry Department, George Washington University School of Medicine and Health Sciences, Washington, DC 20037.
Bailey
J M
JM
D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000818:Animals; D017302:Annexins; D001013:Aorta, Thoracic; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D001241:Aspirin / Q000494:pharmacology*; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors; D003609:Dactinomycin / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D011464:Epoprostenol / Q000096:biosynthesis; D006023:Glycoproteins / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology*; D010455:Peptides / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D015291:Transforming Growth Factors
D000305:Adrenal Cortex Hormones; D017302:Annexins; D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D006023:Glycoproteins; D010455:Peptides; D003609:Dactinomycin; D016718:Arachidonic Acid; D004815:Epidermal Growth Factor; D015291:Transforming Growth Factors; D003907:Dexamethasone; D003513:Cycloheximide; D011464:Epoprostenol; D011451:Prostaglandin-Endoperoxide Synthases; D001241:Aspirin