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Originally published In Press as doi:10.1074/jbc.M410561200 on March 10, 2005 Originally published In Press as doi:10.1074/jbc.M410561200 on March 8, 2005

J. Biol. Chem., Vol. 280, Issue 19, 18579-18589, May 13, 2005
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Interleukin-1{beta} Decreases Expression of the Epithelial Sodium Channel {alpha}-Subunit in Alveolar Epithelial Cells via a p38 MAPK-dependent Signaling Pathway*{boxs}

Jérémie Roux{ddagger}§¶||**, Hisaaki Kawakatsu||{ddagger}{ddagger}, Brandi Gartland{ddagger}§¶||**, Melissa Pespeni{ddagger}§¶||**, Dean Sheppard||{ddagger}{ddagger}, Michael A. Matthay§||**, Cecilia M. Canessa§§, and Jean-François Pittet{ddagger}§¶||**¶¶

From the {ddagger}Laboratory of Surgical Research, the **Cardiovascular Research Institute, the {ddagger}{ddagger}Lung Biology Center, and the Departments of §Anesthesia, Surgery, and ||Medicine, University of California, San Francisco, California 94110 and the §§Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520

Acute lung injury (ALI) is a devastating syndrome characterized by diffuse alveolar damage, elevated airspace levels of pro-inflammatory cytokines, and flooding of the alveolar spaces with protein-rich edema fluid. Interleukin-1{beta} (IL-1{beta}) is one of the most biologically active cytokines in the distal airspaces of patients with ALI. IL-1{beta} has been shown to increase lung epithelial and endothelial permeability. In this study, we hypothesized that IL-1{beta} would decrease vectorial ion and water transport across the distal lung epithelium. Therefore, we measured the effects of IL-1{beta} on transepithelial current, resistance, and sodium transport in primary cultures of alveolar epithelial type II (ATII) cells. IL-1{beta} significantly reduced the amiloride-sensitive fraction of the transepithelial current and sodium transport across rat ATII cell monolayers. Moreover, IL-1{beta} decreased basal and dexamethasone-induced epithelial sodium channel {alpha}-subunit ({alpha}ENaC) mRNA levels and total and cell-surface protein expression. The inhibitory effect of IL-1{beta} on {alpha}ENaC expression was mediated by the activation of p38 MAPK in both rat and human ATII cells and was independent of the activation of {alpha}v{beta}6 integrin and transforming growth factor-{beta}. These results indicate that IL-1{beta} may contribute to alveolar edema in ALI by reducing distal lung epithelial sodium absorption. This reduction in ion and water transport across the lung epithelium is in large part due to a decrease in {alpha}ENaC expression through p38 MAPK-dependent inhibition of {alpha}ENaC promoter activity and to an alteration in ENaC trafficking to the apical membrane of ATII cells.


Received for publication, September 14, 2004 , and in revised form, February 23, 2005.

* This work was supported by National Institutes of Health Grants R01GM62188 and P50HL074005 (to J.-F. P.) and Grant HL51854 (to M. A. M.) and by a fellowship grant from the Cystic Fibrosis Research, Inc. (to J. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

{boxs} The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. A.

¶¶ To whom correspondence should be addressed: Dept. of Anesthesia, San Francisco General Hospital, Rm. 3C-38, 1001 Potrero Ave., San Francisco, CA 94110. Tel.: 415-206-8163; Fax: 415-206-6014; E-mail: pittetj{at}anesthesia.ucsf.edu.


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