NETEA MG, VONK AG, BOERMAN O, JOOSTEN LA, KULLBERG BJ, VAN DER MEER JW; Interscience Conference on Antimicrobial Agents and Chemotherapy (43rd: 2003: Chicago, Ill.).
Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2003 Sep 14-17; 43: abstract no. B-1507.
University Medical Center Nijmegen, Nijmegen, Netherlands.
BACKGROUND: Controversial data are available regarding the role of endogenous intereukin-1 (IL-1) in the mortality due to endotoxemia. We investigated the role of IL-1 in lethal endotoxemia in mice deficient in either IL-1a , IL-1b or IL-1 receptor type I (IL-1RI). METHODS: IL-1a -/-, IL-1b -/-, IL-1RI-/- and control mice were injected i.v. with Escherichia coli LPS (0.25 to 1.0 mg/mouse). Cytokine circulating levels were measured 90 min and 3h after LPS, with survival assessed daily. The kinetics of IL-1a clearance was investigated by i.v. challenge with radioactive [125]I-IL-1a . The expression of IL-1RI and IL-1R accesory protein (IL-1RAcP) in the tissues was measured by quantitative RT-PCR. RESULTS: IL-1b -/- mice were normally susceptible to lethal endotoxaemia, and IL-1a and TNF production did not differ to that in control mice. Surprisingly, when IL-1a -/- mice were challenged with a sublethal LPS dose (0.25 mg), the mortality was higher than that in control mice (90% vs. 10%, p<0.01). The hypothesis that this effect was due to a distorted homeostasis of IL-1RI receptor-mediated pathways was sustained by a strongly decreased clearance of radioactive [125]I-IL-1 injected i.v. into IL-1a -/- mice. A distorted homeostasis of the IL-1 receptors in the tissues of the IL-1a -/- mice was in line with the 40 to 65% reduction of the expression of IL-1RI and IL-1RAcP in the peritoneal macrophages of IL-1a -/- mice. In contrast to the IL-1a -/- and IL-1b -/- mice, IL-1RI-/- mice were completely resistant (0% mortality) when challenged with lethal doses of 1.0 mg LPS (mortality in the control mice 90%, p<0.01). CONCLUSIONS: IL-1RI-mediated signals are crucial in mediating mortality due to lethal endotoxemia. Investigation of IL-1-mediated pathways in IL-1-/- mice is complicated by a distorted homeostasis of IL-1RI and IL-1RAcP expression, resulting in a modified IL-1 clearance, making them less suited for the study of IL-1 effects in experimental models.
Publication Types:
Keywords:
- Animals
- Carrier Proteins
- Cytokines
- Disease Susceptibility
- Endotoxemia
- Interleukin-1
- Interleukin-1 Receptor Accessory Protein
- Interleukin-1beta
- Lipopolysaccharides
- Macrophages, Peritoneal
- Mice
- Mice, Inbred C57BL
- Muridae
- Protein Binding
- Proteins
- Receptors, Interleukin-1
- deficiency
- immunology
Other ID:
UI: 102265287
From Meeting Abstracts