|
rdf:type |
|
|
lifeskim:mentions |
|
|
pubmed:issue |
12
|
|
pubmed:dateCreated |
2010-11-4
|
|
pubmed:abstractText |
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-?) are required for the induction of a pro-inflammatory cytokine profile. We demonstrate that IFN-?-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-?/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.
|
|
pubmed:language |
eng
|
|
pubmed:journal |
|
|
pubmed:citationSubset |
IM
|
|
pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, CD40,
http://linkedlifedata.com/resource/pubmed/chemical/Interferon Regulatory Factor-1,
http://linkedlifedata.com/resource/pubmed/chemical/Interferon Regulatory Factors,
http://linkedlifedata.com/resource/pubmed/chemical/Interferon-gamma,
http://linkedlifedata.com/resource/pubmed/chemical/Interleukin-10,
http://linkedlifedata.com/resource/pubmed/chemical/Interleukin-12,
http://linkedlifedata.com/resource/pubmed/chemical/Janus Kinase 1,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Small Interfering,
http://linkedlifedata.com/resource/pubmed/chemical/STAT1 Transcription Factor,
http://linkedlifedata.com/resource/pubmed/chemical/STAT1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/interferon regulatory factor-8
|
|
pubmed:status |
MEDLINE
|
|
pubmed:month |
Dec
|
|
pubmed:issn |
1873-2968
|
|
pubmed:author |
pubmed-author:ConzelmannMichaelM,
pubmed-author:DregerPeterP,
pubmed-author:FalkChristine SCS,
pubmed-author:GieseThomasT,
pubmed-author:HeckerMarkusM,
pubmed-author:HessMichaelM,
pubmed-author:HildebrandtAnkeA,
pubmed-author:HoAnthony DAD,
pubmed-author:LuftThomasT,
pubmed-author:RodionovaElenaE,
pubmed-author:WagnerAndreas HAH,
pubmed-author:ZotaAnnikaA
|
|
pubmed:copyrightInfo |
Copyright © 2010 Elsevier Inc. All rights reserved.
|
|
pubmed:issnType |
Electronic
|
|
pubmed:day |
15
|
|
pubmed:volume |
80
|
|
pubmed:owner |
NLM
|
|
pubmed:authorsComplete |
Y
|
|
pubmed:pagination |
2074-86
|
|
pubmed:meshHeading |
pubmed-meshheading:20709027-Antigen-Presenting Cells,
pubmed-meshheading:20709027-Antigens, CD40,
pubmed-meshheading:20709027-B-Lymphocytes,
pubmed-meshheading:20709027-Cells, Cultured,
pubmed-meshheading:20709027-Enzyme Activation,
pubmed-meshheading:20709027-Gene Knockdown Techniques,
pubmed-meshheading:20709027-Humans,
pubmed-meshheading:20709027-Interferon Regulatory Factor-1,
pubmed-meshheading:20709027-Interferon Regulatory Factors,
pubmed-meshheading:20709027-Interferon-gamma,
pubmed-meshheading:20709027-Interleukin-10,
pubmed-meshheading:20709027-Interleukin-12,
pubmed-meshheading:20709027-Janus Kinase 1,
pubmed-meshheading:20709027-Leukocytes, Mononuclear,
pubmed-meshheading:20709027-RNA, Small Interfering,
pubmed-meshheading:20709027-STAT1 Transcription Factor,
pubmed-meshheading:20709027-Signal Transduction
|
|
pubmed:year |
2010
|
|
pubmed:articleTitle |
IFN-? activated JAK1 shifts CD40-induced cytokine profiles in human antigen-presenting cells toward high IL-12p70 and low IL-10 production.
|
|
pubmed:affiliation |
German Cancer Research Center, Department of Molecular Oncology/Hematology, Heidelberg, Germany.
|
|
pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
|
