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J. Biol. Chem., Vol. 280, Issue 14, 13538-13544, April 8, 2005

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The Pro-inflammatory Mediator Leukotriene D₄ Induces Phosphatidylinositol 3-Kinase and Rac-dependent Migration of Intestinal Epithelial Cells^*

Sailaja Paruchuri, Oliver Broom, Karim Dib, and Anita Sjölander

From the Experimental Pathology, Department of Laboratory Medicine, Lund University, University Hospital Malmö, SE-205 02 Malmö, Sweden

Inflammatory bowel diseases are associated with increased risk of developing colon cancer. A possible role of the pro-inflammatory leukotriene D₄ (LTD₄) in this process has been implicated by the findings that LTD₄ can signal increased proliferation and survival, both hallmarks of a cancer cell, in non-transformed intestinal epithelial cells. Here we make the novel finding that LTD₄ can also signal increased motility in these cells. In parallel, we found that LTD₄ induced a simultaneous transient 10-fold increase in Rac but not Cdc42 activity. These data were also supported by the ability of LTD₄ to activate the Rac GDP/GTP exchange factor Vav2. Further, LTD₄ triggered a 3-fold transient increase in phosphatidylinositol 3-kinase (PI3K) phosphorylation, a possible upstream activator of the Vav2/Rac signaling pathway. The activation of Rac was blocked by the PI3K inhibitors LY294002 and wortmannin and by transfection of a kinase-negative mutant of PI3K or a dominant-negative form of Vav2. Furthermore, Rac was found to co-localize with actin in LTD₄-generated membrane ruffles that were formed by a PI3K-dependent mechanism. In accordance, the inhibition of the PI3K and Rac signaling pathway also blocked the LTD₄-induced migration of the intestinal cells. The present data reveal that an inflammatory mediator such as LTD₄ cannot only increase proliferation and survival of non-transformed intestinal epithelial cells but also, via a PI3K/Rac signaling pathway, trigger a motile response in such cells. These data demonstrate the capacity of inflammatory mediators to participate in the process by which inflammatory bowel conditions increase the risk for colon cancer development.

Received for publication, August 26, 2004 , and in revised form, December 29, 2004.

^* This work was supported by the grants from the Swedish Cancer Foundation, the Swedish Medical Research Council, the Foundations at Malmö University Hospital, the Ruth and Richard Julins Foundation, Magnus Bergvalls Foundation, Gunnar Nilssons Foundation, and the Österlund Foundation (to A. S.) and from the Royal Physiographic Society in Lund and the Swedish Society for Medical Research (to S. P.). 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.

To whom correspondence should be addressed: Dept. of Laboratory Medicine, Experimental Pathology, Lund University, Malmö University Hospital, Entrance 78, SE-205 02 Malmö, Sweden. Tel.: 46-40-337223; Fax: 46-40-337353; E-mail: anita.sjolander{at}exppat.mas.lu.se.

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