title: Hydrocortisone and indomethacin negatively modulate EGF-R signaling in human fetal intestine.
abstract: Concomitant use of hydrocortisone and the nonspecific cyclo-oxygenase (COX)-inhibitor indomethacin increases the risk for intestinal perforations in preterm infants. We determined whether this was associated with insufficient epidermal growth factor receptor (EGF-R) signaling. We tested the effect of EGF, hydrocortisone, and indomethacin on its activation, cell proliferation and migration, COX-2 expression, and prostaglandin E2 (PGE2) production. Human small intestine epithelial cell line FHsInt74 and EGF-R-deficient mice [EGF-R (-/-)] were used as models. The data revealed that EGF-R signaling had a bimodal positive effect on fetal enterocyte: 1) it increased cell proliferation and migration synergistically with hydrocortisone and 2) up-regulated COX-2 mRNA expression and subsequent PGE2 production. Correlating with this, COX-2 protein expression was down-regulated in EGF-R (-/-) intestine. Despite a positive effect on cell proliferation with EGF, hydrocortisone blunted the stimulatory effect of EGF on COX-2 expression and PGE2 production. Addition of indomethacin even further inhibited the EGF-stimulated PGE2 synthesis. The data suggest that concomitant use of indomethacin and hydrocortisone on preterm infants, who physiologically synthesize only low levels of EGF-R ligands, may lead to intestinal problems related to failure in cytoprotective and regenerative events.
authors.affiliation: Molecular Cancer Biology Program, University of Helsinki, FIN-00014, Finland.
authors.forename: Risto
authors.initials: R
authors.lastname: Kajanne
authors.forename: Sirpa
authors.initials: S
authors.lastname: Leppä
authors.forename: Päivi
authors.initials: P
authors.lastname: Luukkainen
authors.forename: Jarkko
authors.initials: J
authors.lastname: Ustinov
authors.forename: Alexandra
authors.initials: A
authors.lastname: Thiel
authors.forename: Ari
authors.initials: A
authors.lastname: Ristimäki
authors.forename: Päivi J
authors.initials: PJ
authors.lastname: Miettinen
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D020895:Enterocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology*; D007421:Intestine, Small / Q000166:cytology / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation