Listeria monocytogenes modulates macrophage cytokine responses through STAT serine phosphorylation and the induction of suppressor of cytokine signaling 3

Macrophage activation as part of natural resistance to infection is caused by stimulation with IFN-gamma and by the invading microorganisms or microbi al products. Infection of macrophages with the Gram-positive bacterium List eria monocytogenes for short periods before activation with IFN-gamma incre ased the phosphorylation of transcription factor STAT1 at S727 and thereby the expression of IFN-gamma -induced genes. By contrast, persistent infecti on with viable bacteria or treatment with heat-killed Listeria diminished I FN-gamma -stimulated transcription and the phosphorylation of STAT1 at Y701 . Decreased IFN-gamma signaling correlated with the induction of suppressor of cytokine signaling 3 (SOCS3) mRNA and protein. Contrasting our previous findings with LPS, maximal synthesis of SOCS3 required both the immediate signals from Listeria receptors on the cell surface and the activity of a p olypeptide secreted in response to bacterial infection, SOCS3 induction by the secreted protein could not be blocked by neutralizing Abs to IL-10 and it did not require the presence of STAT1, Consistent with the induction of SOCS3 activity, Listeria also inhibited activation of STAT5 by GM-CSF, The p38 mitogen-activated protein kinase was rapidly activated upon infection o f macrophages with L, monocytogenes, Inhibition of p38 mitogen-activated pr otein kinase with the pyridinyl imidazol SB203580 abrogated both STAT1 S727 phosphorylation and the expression of SOCS3, The data suggest that STAT1 s erine kinase and SOCS3 activity are hallmarks of immediate and delayed phas es of influence by bacterial signals on signal transduction in response to IFN-gamma.