Leukotriene D₄ (LTD₄) is a powerful pro-inflammatory mediator, which is formed from arachidonic acid through 5-lipoxygenase (5-LOX). LTD₄ mediates its effects through two specific cell surface receptors, CysLT₁R and CysLT₂R⁽ Reference Heise, O'Dowd and Figueroa ^{1 )}. Colon tumours have an increased expression of CysLT₁R and it has recently been observed that colon cancer patients with high expression levels of this receptor have poor prognosis⁽ Reference Magnusson, Mezhybovska and Lörinc ^{2 )}.

The aim of this study was to investigate the potential role of LTD₄ on the control of non-differentiated intestinal epithelial cell growth using intestinal human Caco-2 cells (HTB37, ATCC) in culture.

We observed that LTD₄ (1–100 nM) induces Caco-2 cell proliferation in a concentration dependent manner. Moreover, cell growth and DNA synthesis induced by LTD₄ were reverted by specific CysLT₁R antagonists, such as MK571 and LY171883, thus indicating the involvement of this receptor in these events.

Considering that LTD₄ up-regulates 5-LOX, cyclooxigenase 2 (COX-2) and CysLT₁R levels in intestinal epithelial cells⁽ Reference Yudina, Parhamifar, Bengtsson, Juhas and Sjölander ^{3 )}, we study the role of COX pathway on the effect of LTD₄ on Caco-2 cell growth. Our findings show that LTD₄ induces PGE₂ synthesis in Caco-2 cell cultures. Moreover, ketoprofen, a COX inhibitor, NS398, a specific COX-2 inhibitor, and SC560, a specific COX-1 inhibitor, were able to inhibit Caco-2 cell growth and DNA synthesis induced by LTD₄. Furthermore, similar effects were obtained using antagonists of PGE₂ receptor, such as SC19220, a specific EP₁ antagonist, and AH23838, a specific EP₄ antagonist.

These data suggest that the proliferative effect of LTD₄ is dependent on PGE₂ synthetized by both COXs and on PGE₂ interaction with EP₁ and EP₄ receptors. Finally, we provide evidence that LTD₄ stimulates several cell signalling pathways involved in cell growth, such as ERK, β-catenin, CREB, and p38α.

On the basis of our results we can conclude that LTD₄ is involved in the regulation of Caco-2 cell growth through the interaction of CysLT₁R and the subsequent PGE₂ synthesis and cell signaling pathways activation. It is hoped that these findings show novel mechanisms by which the effect of LTD₄ on intestinal epithelial cell growth may be mediated.