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

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 gamma. 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.