| Autor: |
Polk, William W., Ellis, Maureen E., Kushlelka, John V., Simmonds, P. Lynne, Woods, Janes S. |
| Předmět: |
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| Zdroj: |
American Journal of Physiology: Cell Physiology; Sep2007, Vol. 293 Issue 3, pC1160-C1170, 3p, 7 Graphs |
| Abstrakt: |
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-κB activation through IKKβ. 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, IκBα phosphorylation, and IKKβ activity following LPS treatment. Prolongation of events associated with NF-κB 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-κB 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-κB activation. Moreover, inhibition of COX-2 activity results in persistent p65-DNA binding, IκBa phosphorylation, and IKKβ 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-κB activation, thereby defining a novel integrated model for regulation of the inflammatory response of kidney epithelial cells to LPS and potentially other external stimuli. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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