Role of IL-6 and TNF in thermoregulation and survival during sepsis in mice

Abstract

Interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) have been implicated as key mediators in inflammation, morbidity, and mortality associated with sepsis. We examined the role of IL-6 and TNF-α signaling on hypothermia, fever, cachexia, anorexia, and survival during sepsis induced by cecal ligation and puncture (CLP) in male and female gene knockout mice. Male wild-type mice developed an initial hypothermia and subsequent fever during sepsis. Male IL-6 knockout mice did not develop fever; rather, they maintained a profound hypothermia during sepsis. Male TNF p55/p75 receptor (TNFR) knockout mice had attenuated hypothermia, but developed a virtually identical fever as wild-type mice. Cachexia did not differ between male wild-type and IL-6 or TNFR knockout mice, whereas anorexia was prolonged in IL-6 knockout mice. Due to the rapid lethality of sepsis in female mice, survival was the only variable we were able to statistically compare among female genotypes. Female wild-type mice had significantly decreased survival compared with male wild-type mice. Survival was significantly enhanced in male and female TNFR knockout mice compared with their wild-type controls. Lack of IL-6 did not affect male or female lethality. These data support the hypothesis that IL-6 is a key mediator of fever and food intake, whereas TNF is responsible for the initial hypothermia and lethality of sepsis in both sexes of mice. The enhanced lethality of CLP-treated female mice supports a role for sex steroids during sepsis.

Group V Phospholipase A2 in Bone Marrow-derived Myeloid Cells and Bronchial Epithelial Cells Promotes Bacterial Clearance after Escherichia coli Pneumonia

“…Our finding are consistent with the observation that IL-6 and TNF-␣ promote post-infection hypothermia in mice (46,47) but are at odds with the findings that IL-10 attenuates the hypothermic response to infection and inhibits LPS-induced production of TNF-␣ and IL-6 (48) and that IL-10 Ϫ/Ϫ mice exhibit more profound hypothermia than IL-10 ϩ/ϩ mice after LPS injection (49), Although our studies have not identified the molecular mechanisms responsible for the more profound hypothermia and systemic inflammation observed in GV Ϫ/Ϫ mice after lung infection with E. coli, they do show that an isolated increase in E. coli in lung parenchyma is sufficient to drive a systemic inflammatory response in these mice, because levels of E. coli in other organs, including liver, spleen, and kidneys as well as arterial blood are similar in GV ϩ/ϩ and GV Ϫ/Ϫ mice after pulmonary E. coli infection.…”

Transglutaminase Type II Is Involved in the Pathogenesis of Endotoxic Shock

“…IL-6 and IFN-␥ were released at significantly high amounts in the early phase after LPS injection both in WT and TG2 Ϫ/Ϫ mice. These molecules are responsible for the development of fever and cachexia (38), the symptoms of endotoxic shock observed initially also in TG2 animals. However, the levels of IL-6, IFN-␥, and G-CSF found at 24 h appear to discriminate between survivors and nonsurvivors, as follows: WT mice had significantly higher, and long lasting, proinflammatory cytokine levels when compared with TG2 Ϫ/Ϫ .…”

Ephedrine hydrochloride inhibits PGN-induced inflammatory responses by promoting IL-10 production and decreasing proinflammatory cytokine secretion via the PI3K/Akt/GSK3β pathway

“…in macrophages. IL-6 and TNF-a have been considered the primary mediators of sepsis, 18 and a positive correlation has been found between multiple organ failure and serum levels of IL-6 and TNF-a. 19,20 Previously, blocking IL-6 was reported to improve the survival of mice in sepsis.…”