title: ROCK activity affects IL-1-induced signaling possibly through MKK4 and p38 MAPK in Caco-2 cells.
abstract: Elevated levels of interleukin-1 (IL-1) accompany inflammatory bowel disease. IL-1-stimulated intestinal epithelial cells can secrete potent chemokines like CXCL8 to exacerbate inflammation. Previously, we found that inhibiting the Rho-associated kinase (ROCK) could inhibit IL-1- or TNF-α-induced CXCL8 secretion by the Caco-2 colonic epithelial cell line. This ROCK inhibition did not affect IκBα phosphorylation and degradation, but suppressed the phosphorylation of c-Jun N-terminal kinase (JNK). Therefore, ROCK must play an important role in epithelial cell CXCL8 responses through an effect on the JNK signaling pathway. Here, we extend these studies by showing that inhibiting ROCK suppressed the IL-1-induced phosphorylation of MKK4, a known activator of JNK, but not MKK7. Yet, ROCK inhibition had no significant effect on the IL-1-induced phosphorylation of extracellular-signal-regulated kinase (ERK) 1/2. Inhibiting ROCK also suppressed the phosphorylation of p38 MAPK after IL-1 stimulation, but this inhibition had no significant effect on the stability of CXCL8 messenger RNA (mRNA) after IL-1 stimulation. These results suggest that ROCK may be important in IL-1-induced signaling through MKK4 to JNK and the activation of p38 MAPK. Finally, inhibiting ROCK in IL-1 and TNF-α co-stimulated Caco-2 cells also resulted in a significant suppression of CXCL8 secretion and mRNA levels suggesting that inhibiting ROCK may be a mechanism to inhibit the overall response of epithelial cells to both cytokines. These studies indicate a novel signaling event, which could provide a target for suppressing intestinal epithelial cells (IEC) chemokine responses involved in mucosal inflammation.
authors.affiliation: Department of Biological Sciences, Binghamton University (SUNY), Binghamton, NY, 13902-6000, USA.
authors.forename: Sayantan
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Department of Biological Sciences, Binghamton University (SUNY), Binghamton, NY, 13902-6000, USA. dmcgee@binghamton.edu.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: McGee
mesh_terms: D000577:Amides / Q000008:administration & dosage; D018938:Caco-2 Cells; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007375:Interleukin-1 / Q000378:metabolism*; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics*; D048670:MAP Kinase Kinase 4 / Q000096:biosynthesis* / Q000235:genetics; D048688:MAP Kinase Kinase 7 / Q000096:biosynthesis / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis* / Q000235:genetics; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D000577:Amides; D007375:Interleukin-1; D016209:Interleukin-8; D011725:Pyridines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C108830:Y 27632; D054460:rho-Associated Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D048688:MAP Kinase Kinase 7; C482559:MAP2K4 protein, human; C482569:MAP2K7 protein, human
keywords: ERK; IL-1; MKK4; ROCK; p38 MAPK