Unphosphorylated STAT3 modulates alpha 7 nicotinic receptor signaling and cytokine production in sepsis.
The role of STAT3 in infectious diseases remains undetermined, in part because unphosphorylated STAT3 has been considered an inactive protein. Here, we report that unphosphorylated STAT3 contributes to cholinergic anti-inflammation, prevents systemic inflammation, and improves survival in sepsis. Bacterial endotoxin induced STAT3 tyrosine phosphorylation in macrophages. Both alpha 7 nicotinic receptor (alpha 7nAChR) activation and inhibition of JAK2 blunt STAT3 phosphorylation. Inhibition of STAT3 phosphorylation mimicked the alpha 7nAChR signaling, inhibiting NF-kappaB and cytokine production in macrophages. Transfection of macrophages with the dominant-negative mutant STAT3F, to prevent its tyrosine phosphorylation, reduced TNF production but did not prevent the alpha 7nAChR signaling. However, inhibition of STAT3 protein expression enhanced cytokine production and abrogated alpha 7nAChR signaling. Alpha 7nAChR controls TNF production in macrophages through a mechanism that requires STAT3 protein expression, but not its tyrosine phosphorylation. In vivo, inhibition of STAT3 tyrosine phosphorylation by stattic prevented systemic inflammation and improved survival in experimental sepsis. Stattic also prevented the production of late mediators of sepsis and improved survival in established sepsis. These results reveal the immunological implications of tyrosine-unphosphorylated STAT3 in infectious diseases.
Peña
Geber
G
Laboratory of Immunity and Infection, Department of Surgery, UMDNJ-New Jersey Medical School, Newark, NJ 07103, USA.
Cai
Bolin
B
Liu
Jun
J
van der Zanden
Esmerij P
EP
Deitch
Edwin A
EA
de Jonge
Wouter J
WJ
Ulloa
Luis
L
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D002460:Cell Line; D003499:Cyclic S-Oxides / Q000008:administration & dosage; D056747:Immunomodulation; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018805:Sepsis / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D019076:Transgenes / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
D000893:Anti-Inflammatory Agents; C579166:Chrna7 protein, mouse; D003499:Cyclic S-Oxides; D050505:Mutant Proteins; D034741:RNA, Small Interfering; D011978:Receptors, Nicotinic; D050796:STAT3 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D064569:alpha7 Nicotinic Acetylcholine Receptor; C517409:stattic