title: The effect of ROCK on TNF-α-induced CXCL8 secretion by intestinal epithelial cell lines is mediated through MKK4 and JNK signaling.
abstract: Intestinal epithelial cells (IEC) play a role in mucosal inflammatory responses by producing important chemokines like CXCL8 when stimulated by TNF-α. Previously, we found that IEC cell lines required the Rho-associated kinase, ROCK, for CXCL8 responses after IL-1 stimulation. This study extends these findings by showing that inhibiting ROCK suppressed TNF-α-induced CXCL8 secretion by Caco-2 and DLD1 colonic epithelial cell lines and CXCL8 mRNA levels in Caco-2 cells. RNAi knockdown experiments indicated that the inhibitory effect was mediated by ROCK2, and not ROCK1. Inhibiting ROCK had no effect on TNF-stimulated IκBα phosphorylation and degradation or p38 MAPK phosphorylation indicating that ROCK plays no role in these signaling pathways. However, inhibiting ROCK suppressed TNF-induced phosphorylation of the p54 JNK isoform and phosphorylation of the upstream MKK4 kinase. These results suggest that ROCK is required for CXCL8 responses by TNF-stimulated IEC by affecting intracellular signaling through MKK4 and JNK.
authors.affiliation: Department of Biological Sciences, Binghamton University (SUNY), Binghamton, NY 13902-6000, USA.
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Perey
authors.affiliation: Department of Biological Sciences, Binghamton University (SUNY), Binghamton, NY 13902-6000, USA.
authors.forename: Isabelle M
authors.initials: IM
authors.lastname: Weishaar
authors.affiliation: Department of Biological Sciences, Binghamton University (SUNY), Binghamton, NY 13902-6000, USA. Electronic address: dmcgee@binghamton.edu.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: McGee
mesh_terms: D000577:Amides / Q000494:pharmacology; D015153:Blotting, Western; D018938:Caco-2 Cells; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007422:Intestines / Q000166:cytology / Q000276:immunology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000276:immunology*; D048670:MAP Kinase Kinase 4 / Q000276:immunology; D010766:Phosphorylation / Q000276:immunology; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference / Q000276:immunology; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000276:immunology*
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D016209:Interleukin-8; D011725:Pyridines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C108830:Y 27632; D054460:rho-Associated Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4
keywords: CXCL8; Intestinal epithelial; JNK; MKK4; ROCK; TNF