Acute alcohol activates STAT3, AP-1, and Sp-1 transcription factors via the family of Src kinases to promote IL-10 production in human monocytes.
Alcohol consumption is associated with an imbalance in pro- and anti-inflammatory cytokines and immunosuppression, partially as a result of enhanced IL-10 production. The mechanisms of IL-10 induction by alcohol remain poorly understood. We identified that increased IL-10 production in human monocytes after acute in vivo alcohol consumption or in vitro alcohol treatment was associated with increased STAT3 activation. Alcohol alone induced and in combination with LPS augmented STAT3 phosphorylation at tyrosine 705 (tyr705) and serine 727 (ser727) residues and increased STAT3 binding to DNA. Upstream, alcohol activated the Src kinases, as indicated by an increase in phosphorylated and a decrease in nonphosphorylated Src proteins. STAT3 activation by Src kinases occurred directly at the tyr705 residue and indirectly at the ser727 residue via JNK MAPKs. Using specific Src (PP2), JNK1/2 (SB600125), or p38 (SB203580) inhibitors, we determined that alcohol treatment alone induced and together with LPS, augmented the DNA-binding capacity of the specificity protein-1 (Sp-1) and AP-1 transcription factors involved in IL-10 production via Src-mediated activation of p38 MAPK and JNK, respectively. Our data suggest that acute alcohol activates Src/STAT3 and Src/MAPK/STAT3, AP-1, and Sp-1 pathways as important mechanisms for IL-10-mediated immunomodulation after acute alcohol use.
Norkina
Oxana
O
University of Massachusetts Medical School, Department of Medicine, LRB 215, 364 Plantation Street, Worcester, MA 01605, USA.
Dolganiuc
Angela
A
Shapiro
Taryn
T
Kodys
Karen
K
Mandrekar
Pranoti
P
Szabo
Gyongyi
G
D000438:Alcohols / Q000494:pharmacology*; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
D000438:Alcohols; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D016329:Sp1 Transcription Factor; D018808:Transcription Factor AP-1; D016753:Interleukin-10; D019061:src-Family Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases