title: PGE2 up-regulates EGF-like growth factor biosynthesis in human granulosa cells: new insights into the coordination between PGE2 and LH in ovulation.
abstract: LH and prostaglandin E(2) (PGE(2)) share many similar effects on the pre-ovulatory follicle. They can induce independently cumulus expansion, the resumption of meiosis and progesterone production. However, cyclooxygenase-2 (COX-2) inhibitors were found to hinder most of the LH-induced effects. Recently, EGF-like growth factors amphiregulin (Ar) and epiregulin (Ep) were found to be produced in response to LH stimulation and to induce cumulus expansion and oocyte maturation. We aimed at evaluating whether PGE(2) induces Ar and Ep syntheses in human granulosa cells and whether the inhibition of PGE(2) production by selective COX-2 inhibitor, nimesulide, affects LH-induced Ar and Ep biosynthesis. Ar and Ep mRNA levels increased following PGE(2) stimulation, in a dose- and time-dependent manner, which resembled those of LH. The blockade of protein kinase A (PKA) (by H89) and mitogen-activated protein kinase (MAPK) (by UO126) reduced the expression of PGE(2)-induced Ar and Ep biosynthesis. Although the stimulation of the cells with LH in the presence of nimesulide did not change the progesterone levels, it resulted in a significant reduction of Ar and Ep biosynthesis. In conclusion, PGE(2) may mimic LH action, at least in part, by the induction of Ar and Ep biosynthesis, which involves cAMP/PKA and MAPK pathways. The negative effect of nimesulide on the ovulatory process may be due to the reduction of Ar and Ep biosynthesis, which implies a possible collaborative role between PGE(2) and LH on their induction.
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: I
authors.initials: I
authors.lastname: Ben-Ami
authors.forename: S
authors.initials: S
authors.lastname: Freimann
authors.forename: L
authors.initials: L
authors.lastname: Armon
authors.forename: A
authors.initials: A
authors.lastname: Dantes
authors.forename: D
authors.initials: D
authors.lastname: Strassburger
authors.forename: S
authors.initials: S
authors.lastname: Friedler
authors.forename: A
authors.initials: A
authors.lastname: Raziel
authors.forename: R
authors.initials: R
authors.lastname: Seger
authors.forename: R
authors.initials: R
authors.lastname: Ron-El
authors.forename: A
authors.initials: A
authors.lastname: Amsterdam
mesh_terms: D000328:Adult; D066258:Amphiregulin; D000818:Animals; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D066260:Epiregulin; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006023:Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D007986:Luteinizing Hormone / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010060:Ovulation / Q000187:drug effects / Q000378:metabolism*; D011374:Progesterone / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; C587849:Areg protein, mouse; D052246:Cyclooxygenase 2 Inhibitors; D066255:EGF Family of Proteins; C587880:EREG protein, human; D066260:Epiregulin; C587881:Ereg protein, mouse; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D013449:Sulfonamides; D011374:Progesterone; D004815:Epidermal Growth Factor; D007986:Luteinizing Hormone; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D015232:Dinoprostone; C012655:nimesulide