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 microbial products. Infection of macrophages with the Gram-positive bacterium Listeria monocytogenes for short periods before activation with IFN-gamma increased the phosphorylation of transcription factor STAT1 at S727 and thereby the expression of IFN-gamma-induced genes. By contrast, persistent infection with viable bacteria or treatment with heat-killed Listeria diminished IFN-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 polypeptide 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 of macrophages with L. monocytogenes. Inhibition of p38 mitogen-activated protein kinase with the pyridinyl imidazol SB203580 abrogated both STAT1 S727 phosphorylation and the expression of SOCS3. The data suggest that STAT1 serine kinase and SOCS3 activity are hallmarks of immediate and delayed phases of influence by bacterial signals on signal transduction in response to IFN-gamma.
Stoiber
D
D
Institute of Microbiology and Genetics, Vienna Biocenter, Vienna, Austria.
Stockinger
S
S
Steinlein
P
P
Kovarik
J
J
Decker
T
T
D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D004789:Enzyme Activation / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology; D020672:I-kappa B Proteins / Q000378:metabolism; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D053613:Janus Kinase 1; D008089:Listeria monocytogenes / Q000276:immunology*; D008264:Macrophages / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000037:antagonists & inhibitors / Q000378:metabolism; D014176:Protein Biosynthesis; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000502:physiology; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D012694:Serine / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D014157:Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases
D016207:Cytokines; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D010455:Peptides; D011506:Proteins; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; C491411:Socs3 protein, mouse; C494080:Stat1 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D019000:Phosphotyrosine; D012694:Serine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011505:Protein-Tyrosine Kinases; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases