STAT4 and STAT6 regulate systemic inflammation and protect against lethal endotoxemia
Alex B. Lentsch, … , Celia Chao, Michael J. Edwards
Alex B. Lentsch, … , Celia Chao, Michael J. Edwards
Published November 15, 2001
Citation Information: J Clin Invest. 2001;108(10):1475-1482. https://doi.org/10.1172/JCI13763.
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Article

STAT4 and STAT6 regulate systemic inflammation and protect against lethal endotoxemia

Abstract

Members of the signal transducer and activator of transcription (STAT) family are transcription factors that mediate many of the effects of pro- and anti-inflammatory cytokines. The progressive systemic inflammatory response induced by endotoxin is mediated by overzealous cytokine production. Here we identify STAT4 and STAT6 as critical regulators of the systemic inflammatory response to endotoxin. Mice deficient for STAT4 or STAT6 were highly susceptible to lethal endotoxemia. In STAT4–/– mice, antibody blockade of IL-12 prevented mortality, suggesting that STAT4 confers protection, while another signaling pathway mediates the detrimental effects of IL-12. In STAT6–/– mice we observed dysregulated activation of the transcription factor NF-κB, resulting in augmented production of proinflammatory cytokines and chemokines. Furthermore, STAT6–/– mice displayed increased organ accumulation of leukocytes and significant hepatocellular injury. These findings demonstrate that STAT4 and STAT6 confer protection against endotoxin-induced death and that for STAT6 these protective effects occur through the regulation of NF-κB activation and subsequent production of proinflammatory cytokines and chemokines.

Authors

Alex B. Lentsch, Atsushi Kato, Brian Davis, Warner Wang, Celia Chao, Michael J. Edwards

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STAT4–/– and STAT6–/– mice are more susceptible to lethal endotoxemia th...
STAT4–/– and STAT6–/– mice are more susceptible to lethal endotoxemia than wild-type mice. Following intraperitoneal administration of 3 mg/kg endotoxin, wild-type, STAT4–/–, and STAT6–/– mice were monitored for survival. Those mice alive at day 7 were alive at day 15 (data not shown). For each group, n = 10−11. *P < 0.05 compared with wild-type mice; †P < 0.05 compared with wild-type and STAT4–/– mice.