Febrile response induced by cecal ligation and puncture (CLP) in rats: involvement of prostaglandin E2 and cytokines

Abstract

The purpose of the present study was to better understand the events involved in the febrile response induced by cecal ligation and puncture (CLP), a complex infectious process. To this end, we conducted in vivo experiments in rats examining (1) fever development, (2) bacterial number in the infection focus and in blood, (3) peripheral and hypothalamic synthesis of cytokines, (4) hypothalamic and cerebrospinal fluid (CSF) synthesis of prostaglandin E(2) (PGE(2)), (5) the effect of anti-IL-6 antibody on fever, and (6) the effect of celecoxib on fever and hypothalamic synthesis of PGE(2) after CLP induction. We found that CLP promotes fever and animal death depending on the number of punctures. The peak of CLP-induced fever overlapped with the maximal increase in the number of bacteria in the infectious focus and blood, which occurred at 6 and 12 h. The peak of the febrile response also coincided with increased amounts of interleukin (IL)-1β, IL-6 and IL-10 in the peritoneal exudate and serum; IL-6 in the hypothalamus and PGE(2) in the CSF and predominantly in the hypothalamus. Moreover, intracerebroventricularly injected anti-IL-6 antibody reduced the febrile response while celecoxib reduced the fever and PGE(2) amount in the hypothalamus induced by CLP. Tumor necrosis factor (TNF)-α peaked at 3 h at all sites studied. Conversely, IL-10 concentration decreased in the hypothalamus. These findings show that the peak of CLP-induced fever is accompanied by an increase of bacteria in peritoneal fluid (local infection) and blood; local synthesis of pyrogenic (IL-1β, IL-6) and antipyretic (IL-10) cytokines and central production of IL-6 and PGE(2), suggesting that these last are the central mediators of this response.

Sepsis-induced morbidity in mice: Effects on body temperature, body weight, cage activity, social behavior and cytokines in brain

“…In the hippocampus and brainstem, only IL-1β protein returned to baseline before the 72 h sample. These findings of an early increase in cytokine protein in mouse brain are consistent with those of a recent study demonstrating increased IL-1β, IL-6 and TNF in hypothalamus of rats as early as 3 – 6 h post CLP (Figueiredo et al 2012). The brain heterogeneity with respect to cytokine responses to CLP may have functional relevance due to the generalized roles of the hypothalamus, hippocampus and brainstem in different physiological and behavioral processes.…”

“…Additional studies with better spatial resolution of cytokine upregulation in brain are necessary before definitive conclusions may be made. It is clear, however, that cytokines are critical mediators of CNS responses to sepsis [e.g., (Gourine et al, 1998; Leon et al, 1998; Figueiredo et al, 2012)]. Previous studies demonstrate that TNF is a key mediator of temperature responses of mice to sepsis, whereas IL-6 is implicated in fever and food intake (Leon et al, 1998).…”

Female Sex Hormones Influence the Febrile Response Induced by Lipopolysaccharide, Cytokines and Prostaglandins but not by Interleukin‐1β in Rats

“…However, TNFRI knockout mice developed a febrile response similar to wild‐type mice after sepsis, suggesting that this receptor is not important for the febrile response in this condition . It should be noted that, particularly in sepsis, the febrile response depends on a massive release of several mediators , which may compensate for the lack of TNF‐α signalling. Alternatively, Roby et al .…”

Exercise activates the hypothalamic S1PR1–STAT3 axis through the central action of interleukin 6 in mice

“…Thus, to reinforce our hypothesis, we developed an experimental strategy to block the IL‐6 action specifically in the third ventricle of the hypothalamus during the exercise by anti‐IL‐6 ICV injections. This approach has been extensively used to block the central action of this cytokine in rodents (Figueiredo et al, ; Le Foll et al, ; Palin et al, ; Timper et al, ). Interestingly, our study demonstrated the anti‐IL‐6 ICV injections, partially reduced the anorexigenic effects of exercise in mice.…”