Kozak Wieslaw, Kluger Matthew J, Soszynski Dariusz, Conn Carole A, Rudolph Karin, Leon Lisa R, Zheng Hui
Lovelace Respiratory Research Institute, P.O. Box 5890, Albuquerque, New Mexico 87185, USA.
Merck Research Laboratory, Department of Genetics and Molecular Biology, Rahway, New Jersey 07065, USA.
Ann N Y Acad Sci. 1998 Sep 29;856:33-47. doi: 10.1111/j.1749-6632.1998.tb08310.x.
Previous data support the hypothesis that during inflammation, interleukin (IL)-1 beta and IL-6 are involved in fever, in activation of the hypothalamic-pituitary-adrenal (HPA) axis, and in the induction of eicosanoids. Most of the pathophysiologic effects of IL-1 beta and Il-6 are mediated by prostaglandins (PGs), modulated by other cytokines, and antagonized by glucocorticoids (GC), a final product of the HPA axis. To further test these relationships, we measured changes in body temperature using biotelemetry in mice deficient in genes for IL-1 beta and/or IL-6 (IL-1 beta knockout [KO] and IL-6 KO) following injection with lipopolysaccharide (LPS) to induce systemic inflammation or turpentine to induce local abscess. Circulating IL-6, tumor necrosis factor alpha (TNF-alpha), GC, and PGE2 were measured in these mice after treatment. IL-1 beta KO mice responded with reduced fever and IL-6 KO mice with normal fever to a high dose of LPS. In contrast, neither type of KO mice produced fever to turpentine. PGE2 levels (measured in the circulation) were suppressed in both types of KO mice injected with turpentine. IL-1 beta KO mice showed deficiency in IL-6 following turpentine, but not LPS, injection. LPS-induced increases in TNF-alpha did not differ between IL-1 beta KO mice and their wild-type counterparts, whereas IL-6 KO mice showed exacerbated LPS-induced circulating TNF-alpha. No differences were noted in plasma elevations of GC between KO and wild-type mice following injection of LPS or turpentine, indicating that IL-1 beta and IL-6 are not required for activation of the HPA axis during inflammation. Our data demonstrate that in the mouse, IL-1 beta and IL-6 are critical for the induction of fever during local inflammation, whereas in systemic inflammation they appear only to contribute to fever.
先前的数据支持这样一种假说，即在炎症过程中，白细胞介素（IL）-1β和IL-6参与发热、下丘脑-垂体-肾上腺（HPA）轴的激活以及类花生酸的诱导。IL-1β和IL-6的大多数病理生理效应由前列腺素（PGs）介导，受其他细胞因子调节，并被HPA轴的终产物糖皮质激素（GC）拮抗。为了进一步验证这些关系，我们在缺乏IL-1β和/或IL-6基因（IL-1β基因敲除[KO]和IL-6 KO）的小鼠中使用生物遥测技术测量体温变化，这些小鼠在注射脂多糖（LPS）以诱导全身炎症或松节油以诱导局部脓肿后。在这些小鼠治疗后测量循环中的IL-6、肿瘤坏死因子α（TNF-α）、GC和前列腺素E2（PGE2）。高剂量LPS刺激后，IL-1β KO小鼠发热反应减弱，而IL-6 KO小鼠发热反应正常。相反，两种基因敲除小鼠对松节油均无发热反应。注射松节油的两种基因敲除小鼠循环中的PGE2水平均受到抑制。注射松节油后，IL-1β KO小鼠IL-6缺乏，但LPS注射后无此现象。LPS诱导的TNF-α升高在IL-1β KO小鼠与其野生型对照之间无差异，而IL-6 KO小鼠LPS诱导的循环TNF-α升高加剧。注射LPS或松节油后，基因敲除小鼠与野生型小鼠血浆GC升高无差异，表明炎症过程中HPA轴的激活不需要IL-1β和IL-6。我们的数据表明，在小鼠中，IL-1β和IL-6在局部炎症期间对发热的诱导至关重要，而在全身炎症中它们似乎仅对发热有一定作用。
