title: TNF transactivation of EGFR stimulates cytoprotective COX-2 expression in gastrointestinal epithelial cells.
abstract: TNF and epidermal growth factor (EGF) are well-known stimuli of cyclooxygenase (COX)-2 expression, and TNF stimulates transactivation of EGF receptor (EGFR) signaling to promote survival in colon epithelial cells. We hypothesized that COX-2 induction and cell survival signaling downstream of TNF are mediated by EGFR transactivation. TNF treatment was more cytotoxic to COX-2(-/-) mouse colon epithelial (MCE) cells than wild-type (WT) young adult mouse colon (YAMC) epithelial cells or COX-1(-/-) cells. TNF also induced COX-2 protein and mRNA expression in YAMC cells, but blockade of EGFR kinase activity or expression inhibited COX-2 upregulation. TNF-induced COX-2 expression was reduced and absent in EGFR(-/-) and TNF receptor-1 (TNFR1) knockout MCE cells, respectively, but was restored upon expression of the WT receptors. Inhibition of mediators of EGFR transactivation, Src family kinases and p38 MAPK, blocked TNF-induced COX-2 protein and mRNA expression. Finally, TNF injection increased COX-2 expression in colon epithelium of WT, but not kinase-defective EGFR(wa2) and EGFR(wa5), mice. These data indicate that TNFR1-dependent transactivation of EGFR through a p38- and/or an Src-dependent mechanism stimulates COX-2 expression to promote cell survival. This highlights an EGFR-dependent cell signaling pathway and response that may be significant in colitis-associated carcinoma.
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Stuart S
authors.initials: SS
authors.lastname: Hobbs
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Goettel
authors.forename: Dongchun
authors.initials: D
authors.lastname: Liang
authors.forename: Fang
authors.initials: F
authors.lastname: Yan
authors.forename: Karen L
authors.initials: KL
authors.lastname: Edelblum
authors.forename: Mark R
authors.initials: MR
authors.lastname: Frey
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Mullane
authors.forename: D Brent
authors.initials: DB
authors.lastname: Polk
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D003106:Colon / Q000166:cytology / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D066246:ErbB Receptors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005753:Gastric Mucosa / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism*; D034741:RNA, Small Interfering; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013270:Stomach / Q000166:cytology; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2; D066246:ErbB Receptors; D019061:src-Family Kinases; D048051:p38 Mitogen-Activated Protein Kinases