ROLE OF IL-6 AND TNF IN THERMOREGULATION AND SURVIVAL DURING SEPSIS IN MICE

Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) have been implicated as key mediators in inflammation, morbidity, and morta lity associated with sepsis. We examined the role of IL-6 and TNF-cr s ignaling on hypothermia, fever, cachexia, anorexia, and survival durin g sepsis induced by cecal ligation and puncture (CLP) in male and fema le gene knockout mice. Male wild-type mice developed an initial hypoth ermia and subsequent fever during sepsis. Male IL-6 knockout mice did not develop fever; rather, they maintained a profound hypothermia duri ng sepsis. Male TNF p55/p75 receptor (TNFR) knockout mice had attenuat ed 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 genot ypes. Female wildtype mice had significantly decreased survival compar ed with male wild-type mice. Survival was significantly enhanced in ma le and female TNFR knockout mice compared with their wild-type control s. Lack of IL-6 did not affect male or female lethality. These data su pport the hypothesis that IL-6 is a key mediator of fever and food int ake, whereas TNF is responsible for the initial hypothermia and lethal ity of sepsis in both sexes of mice. The enhanced lethality of CLP-tre ated female mice supports a role for sex steroids during sepsis.