ACTIVATION OF STAT5 BY LIPOPOLYSACCHARIDE THROUGH GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR PRODUCTION IN HUMAN MONOCYTES

LPS is a potent stimulator of monocytes, inducing many of their functi ons. Although the details of how LPS exerts such functions remain larg ely unknown, transcription factors such as nuclear factor-kappa B, nuc lear factor-IL-6, and activator protein-1 have been shown to be involv ed in this process. However, to date it has been thought that no known STAT molecule plays a role in the activation of monocytes by LPS. In this study we examined whether some known STAT molecule is stimulated by LPS, based on the finding that a GAS motif sequence is conserved in the promoter regions of human, mouse, and rat cyclo-oxygenase-2 (COX- 2) genes. Consequently, LPS induced activation of STAT5 in human monoc ytes, and this STAT5 activation occurred in an indirect way via granul ocyte-macrophage CSF (CM-CSF) secreted by LPS-stimulated monocytes. Ex pression of COX-2 protein was partially reduced by treatment of anti-h uman GM-CSF Ab. Activation of STAT5 was inhibited by either IL-10 or d examethasone (Dex), but not by aspirin. IL-10 blocked activation of ST AT5 indirectly by suppressing CM-CSF production, while Dex inhibited t his activation both directly and indirectly. Taken together, these res ults suggest that in addition to other transcription factors, STAT5 pl ays an important role in activation of monocytes by LPS, and that STAT 5 is another target for IL-10 and Dex to inhibit COX-2 expression in a ctivated monocytes.