| IFN-γ activated JAK1 shifts CD40-induced cytokine profiles in human antigen-presenting cells toward high IL-12p70 and low IL-10 production. | |
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MedLine Citation:
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PMID: 20709027 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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CD40Ligand (CD40L) represents a strong endogenous danger signal associated with chronic inflammatory disease. CD40L induces activation of antigen-presenting cells (APCs) such as DCs, monocytes, B-cells and endothelial cells. However, CD40 activation alone, whilst inducing IL-10 production, is insufficient to induce interleukin (IL)-12p70 release in human APCs suggesting that additional cytokine signals (e.g. GM-CSF, IL-4 or IFN-γ) are required for the induction of a pro-inflammatory cytokine profile. We demonstrate that IFN-γ-induced Janus kinase 1 (JAK1) enhances CD40-induced IL-12p70 release whilst simultaneously inhibiting IL-10 synthesis, resulting in a pro-inflammatory phenotype of CD40L-activated dendritic cells (DCs). JAK2 mediated enhancing effects on IL-12p70 but did not inhibit IL-10 release, whereas Tyk2 mediated inhibitory effects on IL-12p70 release in this system. The mechanism by which complementary IFN-γ/JAK activities affect IL-12p70 production involves STAT1 activation and de novo induction of interferon-responsive factors (IRF)-1 and IRF-8. Simultaneously, JAK1 was unique in inhibiting IL-10 synthesis via STAT1 and IRF-8 with both transcription factors binding to the IL-10 promoter. We demonstrate that CD40- and JAK/STAT/IRF-signalling pathways are strictly complementary for the induction of a pro-inflammatory cytokine profile in human APCs. This suggests that a number of CD40 effects in chronic inflammatory diseases might be weakened by targeting JAK/STAT. |
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Authors:
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Michael Conzelmann; Andreas H Wagner; Anke Hildebrandt; Elena Rodionova; Michael Hess; Annika Zota; Thomas Giese; Christine S Falk; Anthony D Ho; Peter Dreger; Markus Hecker; Thomas Luft |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-08-13 |
Journal Detail:
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Title: Biochemical pharmacology Volume: 80 ISSN: 1873-2968 ISO Abbreviation: Biochem. Pharmacol. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-11-04 Completed Date: 2010-12-15 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0101032 Medline TA: Biochem Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 2074-86 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 Elsevier Inc. All rights reserved. |
Affiliation:
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German Cancer Research Center, Department of Molecular Oncology/Hematology, Heidelberg, Germany. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antigen-Presenting Cells
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metabolism* Antigens, CD40 / pharmacology, physiology* B-Lymphocytes / metabolism Cells, Cultured Enzyme Activation Gene Knockdown Techniques Humans Interferon Regulatory Factor-1 / biosynthesis, genetics Interferon Regulatory Factors / biosynthesis, genetics Interferon-gamma / pharmacology, physiology* Interleukin-10 / biosynthesis* Interleukin-12 / biosynthesis* Janus Kinase 1 / metabolism* Leukocytes, Mononuclear / metabolism RNA, Small Interfering / genetics STAT1 Transcription Factor / genetics, metabolism Signal Transduction |
| Chemical | |
Reg. No./Substance:
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0/Antigens, CD40; 0/Interferon Regulatory Factor-1; 0/Interferon Regulatory Factors; 0/RNA, Small Interfering; 0/STAT1 Transcription Factor; 0/STAT1 protein, human; 0/interferon regulatory factor-8; 130068-27-8/Interleukin-10; 187348-17-0/Interleukin-12; 82115-62-6/Interferon-gamma; EC 2.7.10.1/Janus Kinase 1 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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