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J. Biol. Chem., Vol. 281, Issue 10, 6776-6784, March 10, 2006

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The Inflammatory Mediator Leukotriene D₄ Induces -Catenin Signaling and Its Association with Antiapoptotic Bcl-2 in Intestinal Epithelial Cells^*

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

Increased levels of the inflammatory mediator leukotriene D₄ (LTD₄) are present at sites of inflammatory bowel disease, and such areas also exhibit an increased risk for subsequent cancer development. It is known that LTD₄ affects the expression of many proteins that influence survival and proliferation of intestinal epithelial cells. We demonstrate here that after LTD₄ exposure, -catenin translocates to the nucleus where it signals activation of the TCF/LEF family of transcription factors. These events are mediated via a phosphatidylinositol 3-kinase-dependent phosphorylation of the inhibitory Ser-9 residue of glycogen synthase kinase 3. We also show that in the presence of LTD₄, free -catenin translocates to the mitochondria where it associates with the cell survival protein Bcl-2. We hypothesize that LTD₄ may enhance cell survival via activation of -catenin signaling, in particular, by promoting the association of -catenin with Bcl-2 in the mitochondria. Similar to Wnt-1 signaling, LTD₄ signals an increased level of free -catenin and elevated TCF/LEF promotor activity. This work in intestinal epithelial cells further lends credence to the idea that inflammatory signaling pathways are intrinsically linked with potential oncogenic signals involved in cell survival and apoptosis.

Received for publication, September 12, 2005 , and in revised form, January 4, 2006.

^* This work was supported by grants from the Swedish Cancer Foundation, the Swedish Medical Research Council, the Foundations at Malmö University Hospital, the Ruth and Richard Julin Foundation, Zoega's Foundation, Magnus Bergvall's Foundation, Gunnar Nilsson's Foundation, and the Österlund Foundation (all to A. S.) and by the Royal Physiographic Society in Lund (to M. M.). 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.

¹ To whom correspondence should be addressed. Tel.: 46-40-337-223; Fax: 46-40-337-353; E-mail: anita.sjolander{at}med.lu.se.

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