Molecular mechanisms for IL-10 induced CD14 expression in human monocytic cells

Abstract

IL-10, an immunoregulatory cytokine with biological effects primarily on inhibition of inflammatory responses, has also been shown to stimulate a variety of functions including CD14 expression on human monocytic cells. CD14, a receptor for lipopolysaccharide (LPS), plays a critical role in the synthesis of proinflammatory cytokines by LPS-stimulated monocytic cells. Herein, I show that LPS-induced CD14 expression on monocytic cells may be mediated by endogenously produced IL-10. In this study, I have investigated the molecular mechanisms by which IL-10 enhances CD14 expression in normal human monocytes and a promyelocytic HL-60 cells as a model system. IL-10 induced the phosphorylation of PI3K and p42/44 extracellular signal-regulated kinase (ERK) MAPKs. By employing specific inhibitors for PI3K (LY294002) and ERK MAPKs (PD98059), I provide evidence that LY294002 either alone or in conjunction with PD98059 inhibited IL-10-induced phosphorylation of STAT1 and consequently CD14 expression. However; IL-10-induced STAT3 activation remained unaffected under these conditions. Furthermore, LY294002 and PD98059 inhibited the binding of STAT1 transcription factor to its binding site in the CD14 promoter. Finally, STAT1 siRNA inhibited IL-10-induced CD14 expression. Taken together, results show for the first time that IL-10-mediated CD14 upregulation may be mediated by STATI activation independently of STAT3. Furthermore, IL-10-activated STAT1 may be regulated through PI3K either alone or in concert with the ERK MAPKs.