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J. Biol. Chem., Vol. 278, Issue 46, 45577-45585, November 14, 2003

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Leukotriene D₄ Mediates Survival and Proliferation via Separate but Parallel Pathways in the Human Intestinal Epithelial Cell Line Int 407^*

Sailaja Paruchuri and Anita Sjölander

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

We demonstrated previously that leukotriene D₄ (LTD₄) regulates proliferation of intestinal epithelial cells through a CysLT receptor by protein kinase C (PKC)-dependent stimulation of the mitogen-activated protein kinase ERK1/2. Our current study provides the first evidence that LTD₄ can activate 90-kDa ribosomal S6 kinase (p90^RSK) and cAMP-responsive element-binding protein (CREB) via pertussis-toxin-sensitive G_i protein pathways. Transfection and inhibitor experiments revealed that activation of p90^RSK, but not CREB, is a PKC/Raf-1/ERK1/2-dependent process. LTD₄-mediated CREB activation was not affected by expression of kinase-dead p90^RSK but was abolished by transfection with the regulatory domain of PKC (a specific dominant-inhibitor of PKC). Kinase-negative mutants of p90^RSK and CREB (K^-p90^RSK and K^-CREB) blocked the LTD₄-induced increase in cell number and DNA synthesis (thymidine incorporation). Compatible with these results, flow cytometry showed that LTD₄ caused transition from the G₀/G₁ to the S+G₂/M cell cycle phase, indicating increased proliferation. Similar treatment of cells transfected with K^-p90^RSK resulted in cell cycle arrest in the G₀/G₁ phase, consistent with a role of p90^RSK in LTD₄-induced proliferation. On the other hand, expression of K^-CREB caused a substantial buildup in the sub-G₀/G₁ phase, suggesting a role for CREB in mediating LTD₄-mediated survival in intestinal epithelial cells. Our results show that LTD₄ regulates proliferation and survival via distinct intracellular signaling pathways in intestinal epithelial cells.

Received for publication, March 20, 2003 , and in revised form, August 7, 2003.

^* This work was supported by grants from the Swedish Medical Research Council, the Magnus Bergvall Foundation, the Crafoord Foundation, the Foundations at Malmö University Hospital, the Kock Foundation, and the Zoega Fondation (to A. S.) and by grants from the Royal Physiographic Society in Lund (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. Tel.: 46-40-337223; Fax: 46-40-337353; E-mail: anita.sjolander{at}exppat.mas.lu.se.

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