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.


METHODS
Prospective controlled animal study in a research laboratory.


METHODS
STAT4 and STAT6 knockout mice.


METHODS
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.
Song
Grace Y
GY
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.
Chung
Chun-Shiang
CS
Rhee
Rebecca J
RJ
Cioffi
William G
WG
Ayala
Alfred
A
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D050797:STAT4 Transcription Factor / Q000502:physiology*; D050800:STAT6 Transcription Factor / Q000502:physiology*; D018805:Sepsis / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism
D016207:Cytokines; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor