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

• Published in: Intensive care medicine Vol. 31; no. 11; pp. 1564 - 1569
• Main Authors: SONG, Grace Y, CHUNG, Chun-Shiang, RHEE, Rebecca J, CIOFFI, William G, AYALA, Alfred
• Format: Journal Article
• Language: English
• Published: Heidelberg Springer 01.11.2005; Berlin Springer Nature B.V
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Biological and medical sciences; Blood. Blood and plasma substitutes. Blood products. Blood cells. Blood typing. Plasmapheresis. Apheresis; Care and treatment; Cellular signal transduction; Cytokines; Cytokines - biosynthesis; Diagnosis; Emergency and intensive care: infection, septic shock; Intensive care; Intensive care medicine; Laboratories; Macrophages - drug effects; Macrophages - metabolism; Male; Medical sciences; Mice; Mice, Inbred BALB C; Mortality; Sepsis; Sepsis - immunology; Sepsis - metabolism; Signal Transduction - physiology; Spleen - drug effects; Spleen - metabolism; STAT4 Transcription Factor - physiology; STAT6 Transcription Factor - physiology; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; Transducers, Biomedical; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; United States; Intensive care; Mortality; Rodentia; Morbidity; Infection; Sepsis syndrome; Transducer; Signal transduction; Vertebrata; Mammalia; Mouse; Animal; T-Lymphocyte; Th1 vs. Th2; Cecal ligation and puncture; Lymphocyte; Resuscitation; Macrophage
• DOI: 10.1007/s00134-005-2793-z
• ISSN: 0342-4642

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. Prospective controlled animal study in a research laboratory. STAT4 and STAT6 knockout mice. 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. 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. 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.