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IL-10 Inhibits Cysteinyl Leukotriene-Induced Activation of Human Monocytes and Monocyte-Derived Dendritic Cells

Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892

The immunoregulatory cytokine IL-10 plays an essential role in down-modulating adaptive and innate immune responses leading to chronic inflammatory diseases. In contrast, cysteinyl leukotrienes (cysLTs), important proinflammatory mediators of cell trafficking and innate immune responses, are thought to enhance immune reactions in the pathogenesis of diseases, such as bronchial asthma, atherosclerosis, and pulmonary fibrosis. The aim of this study was to determine the IL-10 regulatory role in cysLT-induced activation of human monocytes and monocyte-derived dendritic cells. Herein we show that cysLT-induced activation and chemotaxis of human monocytes and monocyte-derived immature dendritic cells (iDC) are inhibited by IL-10 pretreatment. IL-10 down-regulated cysLT type 1 and 2 receptors’ mRNA in a time- and concentration-dependent fashion. cysLT-induced activation of monocytes and iDCs measured by intracellular calcium flux and immediate-early gene expression (FBJ murine osteosarcoma viral oncogen homolog B and early growth response-2) was potently decreased by IL-10 and by the cysLT antagonist MK571. Chemotaxis of monocytes and iDCs to increasing concentrations of leukotriene D₄ (LTD₄) was also inhibited by IL-10. LTD₄ enhanced iDC migration in response to CCL5. IL-10 selectively inhibited LTD₄-induced chemotaxis without affecting migration to CCL5. These data indicate that cysLT-induced activation of human monocytes and dendritic cells may be specifically inhibited by IL-10, suggesting a direct link between the 5-lipoxygenase proinflammatory pathway and IL-10 regulatory mechanisms. Antileukotriene therapies may reproduce some regulatory mechanisms played by IL-10 in inflammatory processes.

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¹ Address correspondence and reprint requests to Dr. James H. Shelhamer, Critical Care Medicine Department, Clinical Center, National Institutes of Health, Building 10 Room 2C145, 9000 Rockville Pike, Bethesda, MD 20892. E-mail address: jshelhamer{at}cc.nih.gov

² Abbreviations used in this paper: DC, dendritic cell; cysLTs, cysteinyl leukotrienes; CysLT₁, cysteinyl leukotriene type 1 receptor; CysLT₂, cysteinyl leukotriene type 2 receptor; Egr, early growth response; FosB, FBJ murine osteosarcoma viral oncogene homolog B; iDC, immature dendritic cell; LTC₄, leukotriene C₄; LTD₄, leukotriene D₄; siRNA, short interfering RNA.