Leukotriene D4 induces gene expression in human monocytes through cysteinyl leukotriene type I receptor.

Autor: Woszczek, Grzegorz, Chen, Li-Yuan, Nagineni, Sahrudaya, Kern, Steven, Barb, Jennifer, Munson, Peter J., Logun, Carolea, Danner, Robert L., Shelhamer, James H.
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Zdroj: Journal of Allergy & Clinical Immunology; Jan2008, Vol. 121 Issue 1, p215-221, 7p
Abstrakt: Background: Cysteinyl leukotrienes (CysLTs) are important mediators of innate immune responsiveness and chronic inflammatory diseases. CysLTs acting through CysLT receptors can influence the migration and activity of cells, such as eosinophils, monocytes, and dendritic cells. Objective: We sought to determine the gene expression signature of human monocytes in response to CysLTs and to elucidate the signaling pathways involved in monocyte activation. Methods: Gene expression was analyzed by using oligonucleotide microarrays. Responsiveness to CysLTs was assessed by using real-time PCR, calcium flux, kinase activation, and chemotaxis assays. Results: CysLT type 1 receptor (CysLTR1) transcript 1 is predominantly expressed in human monocytes, and CysLTs signal through CysLTR1 in these cells. Several immediate-early genes, including early growth response 2 and 3, FBJ murine osteosarcoma viral oncogene homolog B, activating transcription factor 3, and nuclear receptor subfamily 4 were significantly induced by leukotriene (LT) D4. This effect was mediated by CysLTR1 coupled to the G protein α inhibitory subunit, activation of phospholipase C, and inositol-1,4,5-triphosphate and store-operated calcium channels. LTD4 induced p38 mitogen-activated protein kinase phosphorylation, a pathway also involved in the regulation of immediate-early gene expression in monocytes. LTD4 stimulated monocyte chemotactic activity that was fully blocked by a selective CysLTR1 inhibitor, MK571, and pertussis toxin, suggesting that CysLTR1 coupled to the G protein α inhibitory subunit is a dominant functional pathway in human monocytes. Conclusion: Our data show that CysLTs acting through CysLTR1 can significantly influence the activation and migration of human monocytes and that these effects can be fully inhibited by CysLTR1 antagonists. [Copyright &y& Elsevier]
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