The purpose of the proposed experiments is to investigate whether interleukin-1beta (IL-1beta) and interleukin-6 (IL-6), which are known to be endogenous pyrogens during lipopolysaccharide (LPS)-induced fever, are also involved in development of fevers during bacterial-induced information and real living bacterial infection. Two hypotheses will be tested using rat and mouse models: 1. IL-1beta is an endogenous pyrogen during bacterial-induced fevers. The pyrogenic action of IL-1beta during bacterial-induced fevers is at the level of the anterior hypothalamus. 2. IL-1beta triggers the release of IL-6 within the anterior hypothalamus to cause fever during bacterial infection and inflammation. To achieve these goals, the effect of intrahypothalamic microinjection of neutralizing antibody to IL- 1beta on bacterial-induced fevers in rats caused by injection of Freund's complete adjuvant (FCA) or cecal ligation and puncture (CLP) will be studied. In experiments in rats, changes in hypothalamic IL-6 concentration during bacterial-induced fevers will be measured in push-pull perfusate using bioassay. It is also planned to investigate the effect of intrahypothalamic injection of neutralizing antibody to IL-1beta on changes in hypothalamic IL-6 concentration during bacterial-induced fevers caused by FCA injection or CLP. It is planned to use IL-1 converting enzyme inhibitor, antibody to IL-6 and to the IL-6 receptor to assess whether intrahypothalamic injections would abolish bacterial-induced fevers. It is also planned to adapt the model of FCA- induced fever to mice with the view of using the resulting model to perform a study of fever in mice deficient in the gene for IL-1beta, IL-1 receptors, IL-1 converting enzyme and IL-6 in response to injection of FCA. Determining the roles of these cytokines in animal models of bacterial-induced fevers will open an opportunity of clinical use of various recombinant tools, that impact positively on the state of the infected patient.
| Gourine, A V; Rudolph, K; Korsak, A S et al. (2001) Role of capsaicin-sensitive afferents in fever and cytokine responses during systemic and local inflammation in rats. Neuroimmunomodulation 9:13-22 |
| Gourine, A V; Rudolph, K; Leon, L R et al. (2000) Effect of interleukin-11 on body temperature in afebrile and febrile rats. Neuroimmunomodulation 8:12-Aug |
| Gourine, A V; Rudolph, K; Tesfaigzi, J et al. (1998) Role of hypothalamic interleukin-1beta in fever induced by cecal ligation and puncture in rats. Am J Physiol 275:R754-61 |
| Gourine, A V; Leon, L R; Rudolph, K et al. (1998) Anterior hypothalamic interleukin-1 receptors are involved in mediation of fever during bacterial sepsis in rats. Ann N Y Acad Sci 856:266-9 |
| Rudolph, K; Gourine, A V; Korsak, A S et al. (1998) Interleukin-6 and tumor necrosis factor-alpha during fever induced by bacterial infection. Ann N Y Acad Sci 856:300-3 |
