Department of Pharmacotherapy, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
Am J Physiol Regul Integr Comp Physiol. 2010 Feb;298(2):R403-10. doi: 10.1152/ajpregu.00395.2009. Epub 2009 Dec 2.
Infection causes the production of proinflammatory cytokines, which act on the central nervous system (CNS) and can result in fever, sleep disorders, depression-like behavior, and even anorexia, although precisely how cytokines regulate the functions of the CNS remain unclear. In the present study, we investigated the regulatory-molecular mechanisms by which cytokines affect hypothalamic function in a state of infection. The intraperitoneal administration of lipopolysaccharide (LPS), a ligand of Toll-like receptor 4 (TLR4), time-dependently (2-24 h) increased signal transducer and activator of transcription 3 (STAT3) phosphorylation in the hypothalamus and liver, which corresponded with anorexia observed within 24 h. Interestingly, the pattern of phosphorylation in response to LPS differed between the hypothalamus and liver. In the hypothalamus, LPS increased STAT3 phosphorylation from 2 h, with a peak at 4 h and a decline thereafter, whereas, in the liver, the peak activation of STAT3 persisted from 2 to 8 h. The time course of the LPS-induced expression of suppressor of cytokine signaling 3 (SOCS3), a STAT3-induced negative regulator of the Janus kinase-STAT pathway, was similar to that of STAT3 phosphorylation. Using mice deficient in myeloid differentiation primary-response protein 88 (MyD88), an adapter protein of TLR4, we found that LPS-induced STAT3 phosphorylation and SOCS3 expression in the hypothalamus and liver were predominantly mediated through MyD88. Moreover, we observed that MyD88-deficient mice were resistant to LPS-induced anorexia. Taken together, our findings reveal a novel mechanism, i.e., MyD88 plays a key role in mediating STAT3 phosphorylation and anorexia in the CNS in a state of infection and inflammation.
感染会导致促炎细胞因子的产生，这些细胞因子作用于中枢神经系统（CNS），可导致发热、睡眠障碍、抑郁样行为，甚至厌食，尽管细胞因子如何调节 CNS 的功能仍不清楚。在本研究中，我们研究了细胞因子影响感染状态下下丘脑功能的调节分子机制。内毒素脂多糖（LPS），Toll 样受体 4（TLR4）的配体，时间依赖性（2-24 小时）增加了下丘脑和肝脏中信号转导和转录激活因子 3（STAT3）的磷酸化，这与 24 小时内观察到的厌食症相对应。有趣的是，LPS 对下丘脑和肝脏的反应模式不同。在下丘脑，LPS 从 2 小时开始增加 STAT3 磷酸化，4 小时达到峰值，随后下降，而在肝脏，STAT3 的峰值激活持续 2-8 小时。LPS 诱导的细胞因子信号转导抑制因子 3（SOCS3）表达的时间过程与 STAT3 磷酸化相似，SOCS3 是 JAK-STAT 通路中 STAT3 诱导的负调节剂。使用髓样分化初级反应蛋白 88（MyD88）缺陷型小鼠，TLR4 的衔接蛋白，我们发现 LPS 诱导的下丘脑和肝脏中的 STAT3 磷酸化和 SOCS3 表达主要通过 MyD88 介导。此外，我们观察到 MyD88 缺陷型小鼠对 LPS 诱导的厌食症有抵抗力。总之，我们的发现揭示了一种新的机制，即 MyD88 在感染和炎症状态下中枢神经系统中介导 STAT3 磷酸化和厌食症中起关键作用。
