Differential induction of BLT receptor expression on human endothelial cells by lipopolysacharide, cytokines, and leukotriene [B.sub.4]

Leukotriene (LT) [B.sub.4] is a powerful chemotactic and immune modulating agent that signals via two receptors denoted [BLT.sub.1] and [BLT.sub.2]. Here we report that [BLT.sub.1] and [BLT.sub.2] are expressed at low levels in an apparently silent state in human umbilical vein endothelial cells (HUVEC). However, treatment with LPS leads to a > 10 fold increase in the levels of [BLT.sub.1] mRNA without any significant effects on [BLT.sub.2] mRNA. In parallel, LPS also increases the amounts of [BLT.sub.1] protein. Tumor necrosis factor-[alpha] (TNF-[alpha]) increases the expression of [BLT.sub.2] mRNA [approximately equal to] 6 times above basal levels with only a modest increase in [BLT.sub.1] mRNA. Interleukin-1 [beta] causes variable and parallel increases of both [BLT.sub.1] and [BLT.sub.2] mRNA. The natural ligand [LTB.sub.4] also increases [BLT.sub.1], but not [BLT.sub.2], mRNA and protein expression. Along with the induction of [BLT.sub.1] and/or [BLT.sub.2], HUVEC acquire the capacity to respond to [LTB.sub.4] with increased levels of intracellular calcium and these signals can be blocked by isotype selective BLT antagonists, CP-105696 and LY-255283. In addition, treatment of HUVEC with [LTB.sub.4] causes increased release of both nitrite, presumably reflecting nitric oxide (NO), and monocyte chemoattractant protein-1. Our data indicate that expression of functional BLT receptors may occur at the surface of endothelial cells in response to LPS, cytokines, and ligand, which in turn may have functional consequences during the early vascular responses to inflammation. Moreover, the results point to BLT receptors as potential targets for pharmacological intervention in LT-dependent inflammatory diseases such as asthma, rheumatoid arthritis, and arteriosclerosis. inflammation | arteriosclerosis | rheumatoid arthritis | asthma | nitric oxide