Growth hormone-induced production of cytokines in murine peritoneal macrophages in vitro: role of JAK/STAT, PI3K, PKC and MAP kinases.
The immunomodulatory properties of growth hormone (GH) are well recognized. Enhanced production of NO and cytokines by macrophages on treatment with GH was reported by us recently. The present investigation elucidates the signaling mechanism(s) by which GH activates macrophages in vitro. It is observed that GH induces the phosphorylation (activation) of JAK2, PI3K, PKC and MAP kinases. Studies with pharmacological inhibitors of various signaling molecules also indicated that GH-induced proinflammatory responses in macrophages are mediated by JAK2/PI3K/PKC/ERK1/2, JAK2/JNK and JAK/STAT signaling cascades. It was further observed that GH induced the enhanced expression/phosphorylation of transcription factors c-fos, c-jun, Elk-1 and Stat1. It is also demonstrated that GH-induced ERK1/2 cascade regulates the production of TNF-alpha and IL-1beta in macrophages, whereas JNK cascade mediated the production of TNF-alpha, IFN-gamma and IL-12. These results suggest that JAK2 plays a central role in mediating proinflammatory responses of macrophages on GH treatment.
Tripathi
Anurag
A
School of Biotechnology, Faculty of Science, Banaras Hindu University, Varanasi 221005, India.
Sodhi
Ajit
A
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D013006:Growth Hormone / Q000276:immunology / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000276:immunology / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000276:immunology / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D015533:Transcriptional Activation; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism
D016207:Cytokines; C494113:Elk1 protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D050807:ets-Domain Protein Elk-1; D013006:Growth Hormone; D019869:Phosphatidylinositol 3-Kinases; D053614:Janus Kinase 2; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3