Impaired induction of IL-10 expression in the lung following hemorrhagic shock.
The balance between pro- and anti-inflammatory cytokines is considered to be an important determinant of the magnitude of inflammation in a number of disease states. We previously showed that resuscitated hemorrhagic shock augmented LPS-induced release of proinflammatory molecules by alveolar macrophages (AM). In the present studies, we evaluated the expression and regulation of the counter inflammatory cytokine IL-10 in the lung using this model. We hypothesized that impaired up-regulation of IL-10 in shock/resuscitated animals might serve as a mechanism contributing to accentuated lung inflammation. In a rodent model, animals exposed to LPS alone exhibited enhanced IL-10 mRNA levels in lung tissue as well as in AM, but antecedent shock/resuscitation delayed and attenuated the LPS-induced IL-10 mRNA levels. The ability of shock to attenuate LPS-stimulated IL-10 was also seen in the protein levels. This effect correlated with an augmented expression of cytokine-induced neutrophil chemoattractant (CINC) mRNA. Shock/resuscitated animals given exogenous IL-10 had reduced proinflammatory response, as shown by decreased expression of CINC mRNA and decreased neutrophil sequestration in the lung. Shock/resuscitation plus LPS markedly reduced the transcription rate of IL-10 mRNA compared to LPS alone but did not affect IL-10 mRNA stability. Reduced IL-10 transcription was not caused solely by impaired nuclear translocation of STAT3 and Sp1/Sp3 transcription factors because LPS-induced nuclear translocation of these factors was augmented by antecedent shock. Considered together, these findings show that shock/resuscitation suppresses LPS-induced IL-10 expression by AM in the lung by inhibiting IL-10 gene transcription. Failed up-regulation of counter inflammatory cytokines may contribute to augmented organ dysfunction in trauma patients.
Khadaroo
Rachel G
RG
Departments of Surgery, University Health Network and University of Toronto, Toronto, Ontario, Canada.
Fan
Jie
J
Powers
Kinga A
KA
Fann
Brand
B
Kapus
Andras
A
Rotstein
Ori D
OD
D000818:Animals; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D019743:Chemokines, CXC / Q000378:metabolism; D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D016753:Interleukin-10 / Q000008:administration & dosage / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009504:Neutrophils / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012151:Resuscitation; D050796:STAT3 Transcription Factor; D012771:Shock, Hemorrhagic / Q000378:metabolism*; D016329:Sp1 Transcription Factor; D051705:Sp3 Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000502:physiology
D019743:Chemokines, CXC; D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D016329:Sp1 Transcription Factor; C497123:Sp3 protein, rat; C494088:Stat3 protein, rat; D015534:Trans-Activators; D014157:Transcription Factors; D016753:Interleukin-10; D051705:Sp3 Transcription Factor