The interleukin-1 (IL-l) system possesses two distinct receptors (type I and type II) which, together with the accessory protein, mediate a multitude of responses to IL-la and IL-l@, including fever. So far, no receptor subtype-specific ligands have been described. Since both types of IL-l receptors occur in the thermoregulatory areas it was unclear which IL-l receptor type mediates fever. We report here that for a series of deletion mutants of human recombinant IL-lb (hrIL-l/I), the affinity of these ligands for the type I IL-1 receptor correlates with their efficacy to evoke the fever response (hrIL-l/I>des-SND 52-54>des-QGE48-50>des-156). Thus, the results suggest that agonist occupancy of the type I IL-l receptor is essential for IL-l/I-mediated fever.

To elucidate the temperature dependence and underlying thermodynamic determinants of the elementary Ca21 release from the sarcoplasmic reticulum, we characterized Ca21 sparks originating from ryanodine receptors (RyRs) in rat cardiomyocytes over a wide range of temperature. From 35 C to 10 C, the normalized fluo-3 fluorescence of Ca21 sparks decreased monotonically, but the D[Ca21]i were relatively unchanged due to increased resting [Ca21]i. The time-to-peak of Ca21 sparks, which represents the RyR Ca21 release duration, was prolonged by 37% from 35 C to 10 C. An Arrhenius plot of the data identified a jump of apparent activation energy from 5.2 to 14.6 kJ/mol at 24.8 C, which presumably reflects a transition of sarcoplasmic reticulum lipids. Thermodynamic analysis of the decay kinetics showed that active transport plays little role in early recovery but a significant role in late recovery of local Ca21 concentration. These results provided a basis for quantitative interpretation of intracellular Ca21 signaling under various thermal conditions. The relative temperature insensitivity above the transitional 25 C led to the notion that Ca21 sparks measured at a "warm room" temperature are basically acceptable in elucidating mammalian heart function.

Subchronic (36 h) exposure of rats to corticosterone (CS) (100 mg/pellet, subcutaneously), blocked the pyrogenic response to recombinant human interleukin 1b (rhIL-1b, 5 mg/kg, ip.). CS treatment reduced the basal mRNA levels of IL-1a and IL-1b, but elevated the mRNA levels of IL-6 in the hypothalamus and hippocampus as shown by RT-PCR. The CS treatment clamped the cytokine mRNA levels, and injection of rhIL-1b to CS treated rats did not significantly affect these altered mRNA levels. IL-6 bioactivity in serum was not significantly changed by CS treatment, but increased 50 times upon injection of rhIL-1b. rhIL-1b caused a significantly lower induction of serum IL-6 levels in CS pretreated rats (9-fold). The pyrogenic response to injection of rhIL-1b has returned 5 days after the removal of the corticosterone pellet, and the hypothalamic cytokine mRNA levels (IL-1a, IL-1b and IL-6) have returned to basal. These results suggest that altered and clamped hypothalamic IL-1a, IL-1b and IL-6 mRNA levels may be involved in the antipyretic effects of a pretreatment with high doses of CS and that these CS effects are rapidly reversible.

Interleukin (IL)-β, IL-β, and tumor necrosis factor 0r (TNF-ot) are considered to act as endogenous pyrogens. Because of the complex pattern of cross-inductions between these cytokines, the relative role of the central and peripheral production of these cytokines in eliciting the fever response has not yet been clarified. The purpose of this study was to determine the role of IL-Β in the fever response by making use of mice carrying a null mutation in the IL-β gene. The intraperitoneal injections oflipopolysaccharide (LPS) (50bLg/kg) and recombinant murine (rm) IL-β (10 bg/kg), respectively, failed to evoke fever response in IL-β-deficient mice, whereas the same doses of LPS and rmIL-βcaused fever response in wild-type mice. The fever response could be induced in the IL-β-deficient mice by intracerebroventricular injection of recombinant human (rh) IL-β (500 ng/mouse), whereas intracerebroventricular injection of rmlL-β (100 ng/mouse) failed to produce fever response in the IL-β-deficient mice. These results suggest that central IL-Β is a necessary component of the fever response to both endogenous (IL-β) and exogenous (LPS) pyrogens in mice and that IL-β acts downstream from both peripheral and central IL-β.

IL-β is an endogenous pyrogen that is inducedduring systemic lipopolysaccharide (LPS)- or IL-1-induced fever. We have examined the fever and cytokineresponses following i.p. injection of IL-1 agonists, IL-1a andIL-β, and compared these with response to LPS (i.p.) in wild-type and IL-β-deficient mice. The IL-β deficient mice appear to have elevated body temperature but exhibit a normal circadian temperature cycle. Exogenously injected IL-β, IL-1a, or LPS induced hyperresponsive fevers in the IL-βdeficient mice. We also observed phenotypic differences between wild-type and IL-β-deficient mice in hypothalamic basal mRNA levels for IL-1a and IL-6, but not for IL-βconverting enzyme or IL-1 receptor type I or type II. The IL-1a mRNA levels were down-regulated, whereas the IL-6 mRNA levels were up-regulated in the hypothalamus of IL-βdeficient mice as compared with wild-type mice. The IL-βdeficient mice also responded to LPS challenge with significantly higher serum corticosterone and with lower serum tumor necrosis factor type a levels than the wild-type mice. The data suggest that, in the redundant cascade of proinflammatory cytokines, IL-β plays an important but not obligatory role in fever induction by LPS or IL-1a, as well as in the induction of serum tumor necrosis factor type a and corticosterone responses either by LPS or by IL-1a or IL-β.