Impaired induction of IL-10 expression in the lung following hemorrhagic shock.

Abstract

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.

• Authors: Rachel G Khadaroo, Jie Fan, Kinga A Powers, Brand Fann, Andras Kapus, Ori D Rotstein
• Journal: Shock (Augusta, Ga.) (Shock) Vol. 22 Issue 4 Pg. 333-9 (Oct 2004) ISSN: 1073-2322 [Print] United States
• PMID: 15377888 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokines, CXC
• DNA-Binding Proteins
• Intercellular Signaling Peptides and Proteins
• Lipopolysaccharides
• RNA, Messenger
• STAT3 Transcription Factor
• Sp1 Transcription Factor
• Sp3 protein, rat
• Stat3 protein, rat
• Trans-Activators
• Transcription Factors
• Interleukin-10
• Sp3 Transcription Factor

Topics

• Animals
• Blotting, Western
• Bronchoalveolar Lavage Fluid (cytology)
• Chemokines, CXC (metabolism)
• DNA-Binding Proteins
• Intercellular Signaling Peptides and Proteins (metabolism)
• Interleukin-10 (administration & dosage, metabolism)
• Lipopolysaccharides (pharmacology)
• Lung (metabolism)
• Macrophages, Alveolar (drug effects, metabolism)
• Male
• Neutrophils (drug effects)
• RNA, Messenger (metabolism)
• Rats
• Rats, Sprague-Dawley
• Resuscitation
• STAT3 Transcription Factor
• Shock, Hemorrhagic (metabolism)
• Sp1 Transcription Factor
• Sp3 Transcription Factor
• Trans-Activators
• Transcription Factors
• Transcription, Genetic (drug effects)
• Up-Regulation (physiology)