4.6 Article Proceedings Paper

IL-4-induced activation of the Stat6 pathway contributes to the suppression of cell-mediated immunity and death in sepsis

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SURGERY
卷 128, 期 2, 页码 133-138

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MOSBY, INC
DOI: 10.1067/msy.2000.107282

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  1. NIGMS NIH HHS [GM46354] Funding Source: Medline

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Background. Although studies have shown that there is a marked depression in cell-mediated (T-H1) immunity after the onset of sepsis, the mechanism by which this occurs remains unknown. In this regard, the T-H2 cytokine IL-4 is known to regulate T-H1 and T-H2 cell responsiveness primarily through the activation of the signal transducer and activation of transcription factor-6 (Stat6) pathway. Methods. We hypothesized that IL-4 may contribute to the suppression of cell-mediated immunity and to death seen in sepsis and that IL-4 may be acting through the Stat6 pathway. To determine this, we induced cecal ligation and puncture (CLP) or sham-CLP in male BALB/c mice. Mice received 2 mg of monoclonal antibody against IL-4 or IgG control ct 12 hours after CLP (ie, at the onset of immune suppression). Splenic T cells were then isolated 24 hours after CLP and stimulated with monoclonal antibody to CD3. Cytokine release and Stat6 phosphorylation (activation) were determined. In a separate group of animals, survival was assessed over 10 days. Results, The results indicate that after CLP, T cells are suppressed in their ability to release the T-H1 cytokines, IL-2 and IFN-gamma. Alternatively, the release of T-H2 cytokines IL-10 and IL-4 is markedly increased after CLP. This was associated with an increase in phosphorylated Stat6 protein. In vivo treatment of mice with monoclonal antibody to IL-4 at 12 hours after CLP restores T-H1 responsiveness while preventing the increase in T-H2 cytokine release and Stat6 phosphorylation. Furthermore, neutralization of IL-4 markedly increased the survival rates in septic animals. Conclusions. Taken together, these data indicate that the T-H2 cytokine IL-4 contributes to the suppression of cell-mediated immunity and death associated with polymicrobial sepsis and suggest that IL-4 may be acting through the Stat6 pathway in septic animals.

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