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

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• 作者：Grzegorz Woszczek ; Li-Yuan Chen ; Sahrudaya Nagineni ; Steven Kern ; Jennifer Barb ; Peter J. Munson ; Carolea Logun ; Robert L. Danner ; James H. Shelhamer
• 关键词：Human monocytes ; cysteinyl leukotrienes ; immediate-early genes ; chemotaxis
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2008
• 出版时间：January 2008
• 年：2008
• 卷：121
• 期：1
• 页码：215-221.e1
• 全文大小：521 K

文摘

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.