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Loss of signal transducer and activator of transduction 4 or 6 signaling contributes to immune cell morbidity and mortality in sepsis

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Abstract

Objective

The role of signal transducer and activator of transduction (STAT) 4 vs. 6 has been assessed thus far only in a model of high mortality strongly driven by proinflammation alone. Their role in a low-mortality (LD25) model of sepsis remains unclear.

Design and setting

Prospective controlled animal study in a research laboratory.

Subjects

STAT4 and STAT6 knockout mice.

Interventions

We induced sepsis by cecal ligation and puncture (CLP) or sham CLP in three groups of mice: (a) STAT4−/−, (b) STAT6−/−, (c) BALB/c. Splenic T cells or macrophages were then harvested 24 h after CLP, and their ability to produce cytokines was assessed.

Results

Following CLP T-cells from BALB/c mice were suppressed in the ability to release the Th1 cytokines interleukin (IL) 2 and interferon γ. The release of Th2 cytokine IL-10 was increased. The Th1 response of STAT4-deficient animals was not only markedly lower in shams but was further suppressed by CLP. The Th2 cytokine response was elevated even more than that of the septic BALB/c. This was associated with lower survival than in the BALB/c. STAT6 deficiency resulted in a stronger Th1 response and a suppressed Th2 response to CLP. A similar difference between IL-12 and IL-10 release was seen in macrophages from these mice. Interestingly, while this resulted in improved survival, compared to STAT4−/− mice, the STAT6−/− animals still had a higher mortality than the BALB/c.

Conclusions

These data suggest that contributions from both STAT4 driven processes as well as STAT6 responses are needed in a balanced fashion to maximize the animals’ ability to survive septic challenge.

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Authors and Affiliations

  1. Shock-Trauma Research Laboratories in the Division of Surgical Research, Department of Surgery, Rhode Island Hospital and Brown University School of Medicine, Providence, RI, 02903, USA

    Grace Y. Song, Chun-Shiang Chung, Rebecca J. Rhee, William G. Cioffi & Alfred Ayala

Authors
  1. Grace Y. Song
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  2. Chun-Shiang Chung
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  3. Rebecca J. Rhee
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  4. William G. Cioffi
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  5. Alfred Ayala
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Corresponding author

Correspondence to Alfred Ayala.

Additional information

This research was supported by grant R01 GM46354 (A.A.) from the National Institutes of Health.

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Song, G.Y., Chung, CS., Rhee, R.J. et al. Loss of signal transducer and activator of transduction 4 or 6 signaling contributes to immune cell morbidity and mortality in sepsis. Intensive Care Med 31, 1564–1569 (2005). https://doi.org/10.1007/s00134-005-2793-z

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  • DOI: https://doi.org/10.1007/s00134-005-2793-z

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