| JAK2 inhibition prevents innate immune responses and rescues animals from sepsis. | |
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MedLine Citation:
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PMID: 20393690 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Sepsis, a leading cause of death in hospitalized patients, is characterized by lethal systemic inflammatory responses. JAK2 is an essential tyrosine kinase modulating immune responses. However, the implications of JAK2 in infectious disorders remain undetermined. Here, we report that JAK2 inhibitors rescue animals from polymicrobial sepsis in a clinically relevant time frame. JAK2 inhibition with AG490 prevents NF-kappaB activation, modulates macrophage activation, and restrains the production of inflammatory cytokines. The inhibition of JAK2 blunted TNF production in both macrophages and splenocytes in a concentration-dependent manner. JAK2 inhibition specifically prevents LPS-induced STAT3 tyrosine phosphorylation without affecting serine phosphorylation in macrophages. JAK2 inhibitor prevents the activation of the canonical p65RelA/p50NF-kappaB1 pathway but not the other NF-kappaB proteins. In vivo, JAK2 inhibition restrains serum TNF levels by modulating TNF production in the lung and the spleen and protects mice from lethal endotoxemia in a concentration-dependent manner. AG490 also inhibits extracellular release of HMGB1 from macrophages and prevents an increase in serum HMGB1 levels during sepsis. JAK2 inhibition started at 24 h after the onset of sepsis rescued the mice from polymicrobial sepsis. Our study is the first experimental evidence that JAK2 inhibitors may provide a pharmacological advantage for the treatment of sepsis in a clinically relevant time frame. |
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Authors:
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Geber Peña; Bolin Cai; Edwin A Deitch; Luis Ulloa |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. |
Journal Detail:
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Title: Journal of molecular medicine (Berlin, Germany) Volume: 88 ISSN: 1432-1440 ISO Abbreviation: J. Mol. Med. Publication Date: 2010 Aug |
Date Detail:
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Created Date: 2010-07-14 Completed Date: 2010-10-25 Revised Date: 2011-09-26 |
Medline Journal Info:
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Nlm Unique ID: 9504370 Medline TA: J Mol Med (Berl) Country: Germany |
Other Details:
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Languages: eng Pagination: 851-9 Citation Subset: IM |
Affiliation:
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Laboratory of Anti-inflammatory Signaling and Surgical Immunology, Center of Immunity and Infection, Department of Surgery, UMDNJ-New Jersey Medical School, Medical Science Building F-673, 185 South Orange Avenue, P.O. Box 1709, Newark, NJ 07103, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Line Cytokines / immunology Enzyme Inhibitors / therapeutic use* HMGB1 Protein / blood Humans Immunity, Innate / drug effects* Janus Kinase 2 / antagonists & inhibitors*, immunology* Macrophages / immunology Male Mice Mice, Inbred C57BL NF-kappa B / immunology STAT3 Transcription Factor / immunology Sepsis / drug therapy* Tumor Necrosis Factor-alpha / immunology Tyrphostins / therapeutic use* |
| Grant Support | |
ID/Acronym/Agency:
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R01 GM084125-02/GM/NIGMS NIH HHS; R01 GM084125-03/GM/NIGMS NIH HHS; R01-GM084125/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cytokines; 0/Enzyme Inhibitors; 0/HMGB1 Protein; 0/NF-kappa B; 0/STAT3 Transcription Factor; 0/Tumor Necrosis Factor-alpha; 0/Tyrphostins; 0/alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; EC 2.7.10.1/Janus Kinase 2 |
| Comments/Corrections | |
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