Document Detail


Attenuated cardiac allograft vasculopathy in mice with targeted deletion of the transcription factor STAT4.
MedLine Citation:
PMID:  10704172     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: To study transcription factor signaling pathways that mediate cardiac allograft vasculopathy, we used mice with targeted gene deletion of signal transducer and activator of transcription (STAT)4 and STAT6 as recipients in our mouse cardiac transplant model of chronic rejection. METHODS AND RESULTS: At day 55 after transplantation, cardiac grafts placed into STAT4 -/- (n=10) had reduced frequency (24+/-2%) and severity (9+/-4%) of vascular occlusion compared with wild-type controls (n=7, frequency 70+/-12% [P<0.001], severity 25+/-6% [P<0.05]). This decrease was associated with reduced intragraft expression ((32)P RT-PCR and immunohistochemistry) of the Th1 signature cytokines interferon-gamma (P<0.001) and interleukin (IL)-2 (P<0.001). Furthermore, cardiac grafts in STAT4 -/- had fewer infiltrating CD45(+) mononuclear cells (99+/-27 cells/mm(3) compared with 551+/-168 cells/mm(3) in wild-type controls [P<0.05]) and reduced expression of P-selectin (P<0.001) and E-selectin (P<0.01) ligand, recently shown to regulate Th1 cell recruitment. In contrast, in grafts placed into STAT6 -/- (n=11), the development of cardiac allograft vasculopathy (frequency 62+/-8%, severity 28+/-6%) and Th2 cytokine profiles (IL-4, IL-10) were comparable to those in wild-type controls. CONCLUSIONS: Hence, we show that immune responses mediated by STAT4, but not STAT6, contribute to the development of cardiac allograft vasculopathy. We speculate that when present, STAT4-mediated signaling pathways may promote cardiac allograft vasculopathy by directing Th1-specific lymphocyte recruitment, activation, and effector functions.
Authors:
J Koglin; T Glysing-Jensen; S Gadiraju; M E Russell
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Circulation     Volume:  101     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2000 Mar 
Date Detail:
Created Date:  2000-03-23     Completed Date:  2000-03-23     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1034-9     Citation Subset:  AIM; IM    
Affiliation:
Cardiovascular Biology Laboratory, Harvard School of Public Health, Boston, MA, USA. joerg.koglin@med1.uni-muenchen.de
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Adhesion / physiology
Coronary Disease / etiology*,  genetics*,  pathology,  physiopathology
Cytokines / physiology
DNA-Binding Proteins / genetics*
Gene Deletion*
Heart Transplantation*
Male
Mice
Mice, Inbred C57BL
Mice, Inbred CBA
Monocytes / pathology,  physiology
Myocardium / metabolism,  pathology
Postoperative Complications*
STAT4 Transcription Factor
STAT6 Transcription Factor
Trans-Activators / genetics*
Grant Support
ID/Acronym/Agency:
HL-59578/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Cytokines; 0/DNA-Binding Proteins; 0/STAT4 Transcription Factor; 0/STAT6 Transcription Factor; 0/Stat4 protein, mouse; 0/Stat6 protein, mouse; 0/Trans-Activators

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