| MyD88 plays a key role in LPS-induced Stat3 activation in the hypothalamus. | |
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MedLine Citation:
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PMID: 19955495 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Yosuke Yamawaki; Hitomi Kimura; Toru Hosoi; Koichiro Ozawa |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-12-02 |
Journal Detail:
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Title: American journal of physiology. Regulatory, integrative and comparative physiology Volume: 298 ISSN: 1522-1490 ISO Abbreviation: Am. J. Physiol. Regul. Integr. Comp. Physiol. Publication Date: 2010 Feb |
Date Detail:
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Created Date: 2010-01-25 Completed Date: 2010-02-17 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 100901230 Medline TA: Am J Physiol Regul Integr Comp Physiol Country: United States |
Other Details:
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Languages: eng Pagination: R403-10 Citation Subset: IM |
Affiliation:
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Department of Pharmacotherapy, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Blotting, Western Brain Chemistry / drug effects Eating / drug effects Hypothalamus / drug effects, metabolism* Interleukin-6 / biosynthesis Lipopolysaccharides / pharmacology* Liver / drug effects, metabolism Male Mice Mice, Inbred C57BL Myeloid Differentiation Factor 88 / physiology* Phosphorylation / drug effects RNA, Messenger / biosynthesis, genetics Reverse Transcriptase Polymerase Chain Reaction STAT3 Transcription Factor / metabolism* Signal Transduction / drug effects Suppressor of Cytokine Signaling Proteins / genetics Toll-Like Receptor 4 / drug effects |
| Chemical | |
Reg. No./Substance:
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0/Interleukin-6; 0/Lipopolysaccharides; 0/Myd88 protein, mouse; 0/Myeloid Differentiation Factor 88; 0/RNA, Messenger; 0/STAT3 Transcription Factor; 0/Socs3 protein, mouse; 0/Suppressor of Cytokine Signaling Proteins; 0/Toll-Like Receptor 4 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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