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. 1997 Mar 18;94(6):2681-6.
doi: 10.1073/pnas.94.6.2681.

Hyperresponsive febrile reactions to interleukin (IL) 1alpha and IL-1beta, and altered brain cytokine mRNA and serum cytokine levels, in IL-1beta-deficient mice

K Alheim  1 , Z Chai, G Fantuzzi, H Hasanvan, D Malinowsky, E Di Santo, P Ghezzi, C A Dinarello, T Bartfai
Affiliations

Hyperresponsive febrile reactions to interleukin (IL) 1alpha and IL-1beta, and altered brain cytokine mRNA and serum cytokine levels, in IL-1beta-deficient mice

K Alheim et al. Proc Natl Acad Sci U S A. .

Abstract

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

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Figures

Figure 1
Figure 1
(A–C) Diurnal temperature rhythm and LPS-induced fever in IL-1β-deficient and wild-type mice and measurement of the core body temperature of IL-1β-deficient (−/−) and wild-type (+/+) mice, measured at 30 ± 1°C of ambient temperature. (A) Recordings of basal temperatures of the animals for 24 h. •, IL-1β-deficient mice (n = 36); and ○, wild-type mice (n = 36). One-hour average (mean ± SE) of temperature recordings over 24 h are shown. ∗, P < 0.05, wild-type vs. IL-1β-deficient mice. (B) Injection of LPS (100 μg per kg of body weight, i.p.) or saline. Effects on body temperature in saline-injected IL-1β-deficient mice (n = 8; •), saline-injected wild-type mice (n = 9; ○), LPS-injected IL-1β-deficient mice (n = 4; ▪), and LPS-injected wild-type mice (n = 5; □). Injection at time 0. Data were recorded at 10-min intervals and are presented as mean ± SE. ∗∗, P < 0.01, LPS-injected IL-1β-deficient vs. saline-injected IL-1β-deficient mice; ##, P < 0.01, and #, P < 0.05, LPS-injected wild-type vs. saline-injected wild-type mice; and §§, P < 0.01, LPS-injected wild-type vs. LPS-injected IL-1β-deficient mice. (C) Injection of LPS (5 mg per kg of body weight, i.p.) or saline. Effects on body temperature in saline-injected IL-1β-deficient mice (n = 8; •), saline-injected wild-type mice (n = 9; ○), LPS-injected IL-1β-deficient mice (n = 3; ▪), and LPS-injected wild-type mice (n = 3; □). Injection at time 0. One-hour average (mean ± SE) of temperature recordings, over 48 h, are shown. ∗∗, P < 0.01, and ∗, P < 0.05, LPS-injected IL-1β-deficient vs. saline-injected IL-1β-deficient mice; #, P < 0.05, LPS-injected wild-type vs. saline-injected wild-type mice; and §, P < 0.05, LPS-injected wild-type vs. LPS-injected IL-1β-deficient mice.
Figure 2
Figure 2
(A–C) IL-1α- and IL-1β-induced fever responses in IL-1β-deficient and wild-type mice. Effect of injections on the core body temperature of IL-1β-deficient (−/−) and wild-type (+/+) mice, measured at 30 ± 1°C of ambient temperature. (A) Injection of rrIL-1α (25 μg per kg of body weight, i.p.) or saline. Effects on body temperature in saline-injected IL-1β-deficient mice (n = 8; •), saline-injected wild-type mice (n = 9; ○), rrIL-1α-injected IL-1β-deficient mice (n = 4; ♦), and rrIL-1α-injected wild-type mice (n = 4; ⋄). Injection at time 0. Data were recorded at 10-min intervals and are presented as mean ± SE. ∗∗, P < 0.01, IL-1α-injected IL-1β-deficient vs. saline-injected IL-1β-deficient mice; ##, P < 0.01, and #, P < 0.05, IL-1α-injected wild-type vs. saline-injected wild-type mice; and §§, P < 0.01, and §, P < 0.05, IL-1α-injected wild-type vs. IL-1α-injected IL-1β-deficient mice. (B) Injection of rrIL-1β (50 μg per kg of body weight, i.p.) or saline. Effects on body temperature in saline-injected IL-1β-deficient mice (n = 8; •), saline-injected wild-type mice (n = 9; ○), rrIL-1β-injected IL-1β-deficient mice (n = 5; ▴), and rrIL-1β-injected wild-type mice (n = 5; ▵). Injection at time 0. Data were recorded at 10-min intervals and are presented as mean ± SE. ∗∗, P < 0.01, IL-1β-injected IL-1β-deficient vs. saline-injected IL-1β-deficient mice; ##, P < 0.01, IL-1β-injected wild-type vs. saline-injected wild-type mice; §, P < 0.05, IL-1β-injected wild-type vs. IL-1β-injected IL-1β-deficient mice. (C) Injection of rrIL-1β (100 μg per kg of body weight, i.p.) or saline. Effects on body temperature in saline-injected IL-1β-deficient mice (n = 8; •), saline-injected wild-type mice (n = 9; ○), rrIL-1β-injected IL-1β-deficient mice (n = 4; ▴), and rrIL-1β-injected wild-type mice (n = 4; ▵). Injection at time 0. Data were recorded at 10-min intervals and are presented as mean ± SE. ∗∗, P < 0.01, and ∗, P < 0.05, IL-1β-injected IL-1β-deficient vs. saline-injected IL-1β-deficient mice; ##, P < 0.01, IL-1β-injected wild-type vs. saline-injected wild-type mice; and §, P < 0.05, IL-1β-injected wild-type vs. IL-1β-injected IL-1β-deficient mice; and ¤, P < 0.05, saline-injected wild-type vs. saline-injected IL-1β-deficient mice.
Figure 3
Figure 3
(A) Serum corticosterone levels in IL-1β-deficient mice (−/−) and wild-type mice (+/+) after injection of rrIL-1α (10 μg per kg of body weight, i.p.) [IL-1α]; rrIL-1β (10 μg per kg of body weight, i.p.) [IL-1β]; LPS (5 mg per kg of body weight, i.p.) [LPS]; or saline [contr]. ∗∗, P < 0.01 vs. control +/+; ##, P < 0.01 vs. control −/−; and ¶¶, P < 0.01 vs. LPS +/+. Control +/+, n = 12; control −/−, n = 12; IL-1α +/+, n = 4; IL-1α −/−, n = 3; IL-1β +/+, n = 5; IL-1β −/−, n = 5; LPS +/+, n = 7; and LPS −/−, n = 7. (B) Serum IL-6 levels in IL-1β-deficient mice (−/−) and wild-type mice (+/+), after injection of rrIL-1α (10 μg per kg of body weight, i.p.) [IL-1α]; rrIL-1β (10 μg per kg of body weight, i.p.) [IL-1β]; LPS (5 mg per kg of body weight, i.p.) [LPS]; or saline [contr]. ∗∗, P < 0.01 vs. control +/+; ##, P < 0.01 vs. control −/−; ¤¤, P < 0.01, vs. IL-1α +/+. Control +/+, n = 12; control −/−, n = 12; IL-1α +/+, n = 4; IL-1α −/−, n = 3; IL-1β +/+, n = 5; IL-1β −/−, n = 5; LPS +/+, n = 7; and LPS −/−, n = 7. (C and D) Serum TNFα levels in IL-1β-deficient mice (−/−) and wild-type mice (+/+). (C) TNFα levels in serum after injection of LPS (5 mg per kg of body weight, i.p.) [LPS] or saline [contr]. ∗∗, P < 0.01, vs. control +/+; ##, P < 0.01, vs. control −/−; and ¶¶, P < 0.01, vs. LPS +/+. Control +/+, n = 12; control −/−, n = 12; LPS +/+, n = 7; and LPS −/−, n = 7. Note that the scale on the ordinate is 10-fold higher than in D. (D) TNFα levels in serum after injection of rrIL-1α (10 μg per kg of body weight, i.p.) [IL-1α]; rrIL-1β (10 μg per kg of body weight, i.p.) [IL-1β]; or saline [contr]. ∗∗, P < 0.01, vs. contr +/+; ##, P < 0.01, vs. control −/−; ¤, P < 0.05, vs. IL-1α +/+; and +, P < 0.05, vs. IL-1β +/+. Control +/+, n = 12; control −/−, n = 12; IL-1α +/+, n = 5; IL-1α −/−, n = 5; IL-1β +/+, n = 5; and IL-1β −/−, n = 5.
Figure 4
Figure 4
(A–C) Relative mRNA levels in hypothalamus of IL-1β-deficient mice (−/−) and wild-type mice (+/+), after injection of LPS (5 mg per kg of body weight, i.p.) [LPS]; rrIL-1α (10 μg per kg of body weight, i.p.) [IL-1α]; rrIL-1β (10 μg per kg of body weight, i.p.) [IL-1β]; or saline [contr]. Ratios of respective mRNA and β-actin mRNA are presented. ∗∗, P < 0.01, and ∗, P < 0.05, vs. control +/+; and ¤, P < 0.05, vs. IL-1α +/+. (A) IL-1α mRNA levels. Control +/+, n = 7; control −/−, n = 7; LPS +/+, n = 3; LPS −/−, n = 3; IL-1α +/+, n = 3; IL-1α −/−, n = 3; IL-1β +/+, n = 5; IL-1β −/−, n = 5. (B) IL-6 mRNA levels. Control +/+, (n = 7); control −/−, (n = 7); LPS +/+, n = 3; LPS −/−, n = 3; IL-1α +/+, n = 3; IL-1α −/−, n = 3; IL-1β +/+, n = 5; and IL-1β −/−, n = 5. (C) TNFα mRNA levels. Control +/+, n = 8; control −/−, n = 7; LPS +/+, n = 3; LPS −/−, n = 3; IL-1α +/+, n = 3; IL-1α −/−, n = 3; IL-1β +/+, n = 5; and IL-1β −/−, n = 5.
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