RhoA regulation of NF-kappaB activation is mediated by COX-2-dependent feedback inhibition of IKK in kidney epithelial cells
| Autor: | James S. Woods, John V. Kushleika, William W. Polk, P. Lynne Simmonds, Maureen E. Ellis |
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| Rok vydání: | 2007 |
| Předmět: |
Lipopolysaccharides
medicine.medical_specialty RHOA Lipopolysaccharide Transcription Genetic Physiology MAP Kinase Kinase Kinase 1 Inflammation IκB kinase Cell Line chemistry.chemical_compound Internal medicine medicine Animals Feedback Physiological Kidney Nephritis biology JNK Mitogen-Activated Protein Kinases Transcription Factor RelA Epithelial Cells Cell Biology Epithelium I-kappa B Kinase Rats Transcription Factor AP-1 Endocrinology medicine.anatomical_structure Kidney Tubules chemistry Cell culture Cyclooxygenase 2 biology.protein Cancer research medicine.symptom Signal transduction rhoA GTP-Binding Protein Signal Transduction |
| Zdroj: | American journal of physiology. Cell physiology. 293(3) |
| ISSN: | 0363-6143 |
| Popis: | Numerous studies have demonstrated a central role of renal tubular epithelial cells in the etiology of kidney injury and disease through the elaboration of inflammatory mediators. However, little is known about the cellular signaling mechanisms involved in this process. In this study we employed normal rat kidney epithelial (NRK52E) cells to identify a novel LPS-induced signaling pathway in which RhoA-mediated AP-1 activity promotes expression of cyclooxygenase-2 (COX-2) with consequent feedback inhibition of NF-kappaB activation through IKKbeta. Inhibition of RhoA signaling using either the RhoA kinase inhibitor Y-27632 or a dominant negative mutant of RhoA (RhoA-DN) dramatically extended the duration of p65-DNA binding, IkappaBalpha phosphorylation, and IKKbeta activity following LPS treatment. Prolongation of events associated with NF-kappaB activation was also observed in cells pretreated and/or cotransfected with the JNK inhibitor SP600125 or deletion mutants of MEKK1 (MEKK1-KD) or Jun (Jun-DN). Conversely, constitutive expression of RhoA prevented NF-kappaB activation by LPS, and this effect was reversed by cotransfection with MEKK1-KD. In addition, we found that the RhoA/AP-1 signaling axis plays a necessary role in COX-2 expression by LPS and that this effect is independent of NF-kappaB activation. Moreover, inhibition of COX-2 activity results in persistent p65-DNA binding, IkappaBalpha phosphorylation, and IKKbeta activity, similar to that observed after prevention of RhoA/AP-1 axis signaling. These findings suggest that COX-2 links the RhoA/AP-1 signaling cascade to NF-kappaB activation, thereby defining a novel integrated model for regulation of the inflammatory response of kidney epithelial cells to LPS and potentially other external stimuli. |
| Databáze: | OpenAIRE |
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