The interleukin-1 system: receptors, ligands, and ICE in the brain and their involvement in the fever response

Abstract

The ligands and the receptors of the interleukin 1 (IL-1) system constitute a highly inducible set of proteins whose expression in infection and inflammation is of key importance in the host defense. The IL-1 system participates in the stimulation of the immune system, the neuroendocrine system, and the neuroimmune system. The major soluble and secreted agonist of the system, IL-1 beta, has been studied by mutational and transgenic approaches. Furthermore, involvement of the signal-transducing type I IL-1 receptor (IL-1RI), in fever and other responses, has been studied by null mutation technique. We describe the inducible expression of the two agonists, IL-1 alpha (31 kDa and 17 kDa) and IL-1 beta (17 kDa) and of the IL-1 receptor subtypes IL-1RI and IL-1RII in the brain and in the adrenals (as well as in the pituitary cell line AtT20). We also describe an additional member of the IL-1 family: the IL-1 receptor antagonist (IL-1ra), an endogenous antagonist to IL-1 alpha and IL-1 beta. Furthermore, the IL-1 beta-converting enzyme (ICE) and its differential regulation and expression in brain and adrenals is also discussed. Fever is a systemic response to intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) injection of IL-1 alpha or IL-1 beta. IL-1 beta-induced fever can be blocked by IL-1ra pretreatment. The fever response seems to be mediated via the IL-1RI as inferred from studies with receptor subtype-specific mutants of IL-1 beta and from studies in IL-1RI knock-out (IL-1RI KO) mice. IL-1 beta knock-out mice showed a hyperresponsive fever to both IL-1 agonists, IL-1 alpha and IL-1 beta, as well as to LPS.