A PI-3 kinase-dependent, Stat1-independent signaling pathway regulates interferon-stimulated monocyte adhesion.
Type I interferon (IFN)-alpha/beta and type II IFN-gamma induce the expression of early response genes through activation of the Janus tyrosine kinase/signal transducer and activator of transcription (Stat) pathway. Although IFNs regulate a variety of other signaling cascades, little is known about how they contribute to the biological activities of these cytokines. In this study, we demonstrate that IFN-beta or IFN-gamma induces the phosphorylation of the serine/threonine kinase Akt in primary human peripheral blood monocytes. Abrogation of the IFN-stimulated Akt activation by phosphatidylinositol-3 kinase (PI-3K) inhibitors prevents IFN-induced adhesion in these cells, and IFN activation of the Stat1-dependent guanylate-binding protein (GBP) gene is not affected. Importantly, Stat1-deficient bone marrow macrophages displayed a similar level of IFN-gamma-stimulated adhesion compared with macrophages derived from wild-type littermates. These findings demonstrate for the first time that IFN stimulation of a PI-3K signaling cascade modulates the ability of these cytokines to regulate monocyte adhesion, and this process does not require the expression of Stat1, a primary mediator of IFN-gamma signaling.
Navarro
Angels
A
Department of Immunology, Lerner Research Institute, Ohio, USA.
Anand-Apte
Bela
B
Tanabe
Yoshinari
Y
Feldman
Gerald
G
Larner
Andrew C
AC
D000818:Animals; D015152:Blotting, Northern; D001854:Bone Marrow Cells; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012259:Ribonuclease, Pancreatic / Q000378:metabolism; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism*
D002867:Chromones; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D019204:GTP-Binding Proteins; D016899:Interferon-beta; D007371:Interferon-gamma; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012259:Ribonuclease, Pancreatic; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; C490287:GBP1 protein, human; C490288:Gbp2b protein, mouse; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494918:AKT1 protein, human