Interleukin‐1 System: Receptors, Ligands, and ICE in the Brain and Their Involvement in the Fever Response

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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‐1β, 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‐1α (31 kDa and 17 kDa) and IL‐1β (17 kDa) 1, 2 and of the IL‐1 receptor subtypes IL‐1RI and IL‐1RII 3 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), 4 an endogenous antagonist to IL‐1α and IL‐1β. Furthermore, the IL‐1β‐converting enzyme (ICE) and its differential regulation and expression in brain and adrenals is also discussed. 5 Fever is a systemic response to intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) injection of IL‐1α or IL‐1β. IL‐1β‐induced fever can be blocked by IL‐1ra pretreatment. 6 The fever response seems to be mediated via the IL‐1RI as inferred from studies with receptor subtype‐specific mutants of IL‐1β 7 and from studies in IL‐1RI knock‐out (IL‐1RI KO) mice. 8 IL‐1β knock‐out mice showed a hyperresponsive fever to both IL‐1 agonists, IL‐1α and IL‐1β, as well as to LPS. 2