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J. Biol. Chem., Vol. 279, Issue 36, 37597-37612, September 3, 2004

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Aeromonas hydrophila Cytotoxic Enterotoxin Activates Mitogen-activated Protein Kinases and Induces Apoptosis in Murine Macrophages and Human Intestinal Epithelial Cells^*

Cristi L. Galindo, Amin A. Fadl, Jian Sha, Celso Gutierrez, Jr., Vsevolod L. Popov¶, Istvan Boldogh, Bharat B. Aggarwal||, and Ashok K. Chopra**

From the Departments of Microbiology & Immunology and ^¶Pathology, University of Texas Medical Branch, Galveston, Texas 77555-1070 and the ^||Department of Immunotherapy, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030-4095

A cytotoxic enterotoxin (Act) of Aeromonas hydrophila possesses several biological activities, induces an inflammatory response in the host, and causes apoptosis of murine macrophages. In this study, we utilized five target cell types (a murine macrophage cell line (RAW 264.7), bone marrow-derived transformed macrophages, murine peritoneal macrophages, and two human intestinal epithelial cell lines (T84 and HT-29)) to investigate the effect of Act on mitogen-activated protein kinase (MAPK) pathways and mechanisms leading to apoptosis. As demonstrated by immunoprecipitation/kinase assays or Western blot analysis, Act activated stress-associated p38, c-Jun NH₂-terminal kinase (JNK), and extracellular signal-regulated kinase 1/2 (ERK1/2) in these cells. Act also induced phosphorylation of upstream MAPK factors (MAPK kinase 3/6 (MKK3/6), MKK4, and MAP/ERK kinase 1 (MEK1)) and downstream effectors (MAPK-activated protein kinase-2, activating transcription factor-2, and c-Jun). Act evoked cell membrane blebbing, caspase 3-cleavage, and activation of caspases 8 and 9 in these cells. In macrophages that do not express functional tumor necrosis factor receptors, apoptosis and caspase activities were significantly decreased. Immunoblotting of host whole cell lysates revealed Act-induced up-regulation of apoptosis-related proteins, including the mitochondrial proteins cytochrome c and apoptosis-inducing factor. However, mitochondrial membrane depolarization was not detected in response to Act. Taken together, the data demonstrated for the first time Act-induced activation of MAPK signaling and classical caspase-associated apoptosis in macrophages and intestinal epithelial cells. Given the importance of MAPK pathways and apoptosis in inflammation-associated diseases, this study provided new insights into the mechanism of action of Act on host cells.

Received for publication, April 27, 2004 , and in revised form, June 21, 2004.

^* This work was supported by National Institutes of Health NIAID Grant AI41611. 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.

Predoctoral fellow supported by the National Science Foundation.

^** To whom correspondence should be addressed: Dept. of Microbiology and Immunology, Medical Research Building, 301 University Blvd., University of Texas Medical Branch, Galveston, TX 77555-1070. Tel.: 409-747-0578; Fax: 409-747-6869; E-mail: achopra{at}utmb.edu.

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