Document Detail


MyD88 plays a key role in LPS-induced Stat3 activation in the hypothalamus.
MedLine Citation:
PMID:  19955495     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Yosuke Yamawaki; Hitomi Kimura; Toru Hosoi; Koichiro Ozawa
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-12-02
Journal Detail:
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:
Created Date:  2010-01-25     Completed Date:  2010-02-17     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100901230     Medline TA:  Am J Physiol Regul Integr Comp Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  R403-10     Citation Subset:  IM    
Affiliation:
Department of Pharmacotherapy, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
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MeSH Terms
Descriptor/Qualifier:
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:
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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