Document Detail


Effect of hydrodynamics-based gene delivery of plasmid DNA encoding interleukin-1 receptor antagonist-Ig for treatment of rat autoimmune myocarditis: possible mechanism for lymphocytes and noncardiac cells.
MedLine Citation:
PMID:  15795329     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Interleukin-1 (IL-1) is a powerful and important cytokine in myocarditis. The purpose of this study was to evaluate the effect and possible mechanism of hydrodynamics-based delivery of the IL-1 receptor antagonist (IL-1RA)-immunoglobulin (Ig) gene for treatment of rat experimental autoimmune myocarditis (EAM). METHODS AND RESULTS: On the day after immunization, rats were transfected with either pCAGGS encoding IL-1RA-Ig or pCAGGS encoding Ig alone. On day 17, IL-1RA-Ig gene therapy was effective in controlling EAM, as monitored by a decreased ratio of heart weight to body weight, reduced myocarditis areas, reduced gene expression of atrial natriuretic peptide in hearts, and improved cardiac function in echocardiographic and hemodynamic parameters. Examination of the expression of IL-1-related genes in purified cells from EAM hearts suggested that ectopic IL-1RA-Ig-acting target cells were alphabetaT cells and noncardiomyocytic noninflammatory cells such as fibroblasts, smooth muscle cells, and endothelial cells. Therefore, we examined the effect of serum containing IL-1RA-Ig on the expression of immune-relevant genes within noncardiomyocytic cells cultured from EAM hearts or concanavalin A-stimulated lymphocytes derived from lymph nodes in EAM-affected rats. The expression of immunologic molecules (prostaglandin E synthase, cyclooxygenase-2, and IL-1beta) in cultivated noncardiomyocytic cells and Th1 cytokines (IL-2 and IFN-gamma) in lymphocytes was significantly decreased by the serum containing IL-1RA-Ig. CONCLUSIONS: EAM was suppressed by hydrodynamics-based delivery of plasmid DNA encoding IL-1RA-Ig. In addition, IL-1RA-Ig suppressed gene expression of prostaglandin synthases and IL-1 in noncardiomyocytic cells and Th1 cytokines in lymphocytes.
Authors:
Hui Liu; Haruo Hanawa; Tsuyoshi Yoshida; Raafat Elnaggar; Manabu Hayashi; Ritsuo Watanabe; Ken Toba; Kaori Yoshida; He Chang; Yuji Okura; Kiminori Kato; Makoto Kodama; Hiroki Maruyama; Junichi Miyazaki; Mikio Nakazawa; Yoshifusa Aizawa
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Publication Detail:
Type:  Journal Article     Date:  2005-03-28
Journal Detail:
Title:  Circulation     Volume:  111     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2005 Apr 
Date Detail:
Created Date:  2005-04-06     Completed Date:  2005-10-28     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1593-600     Citation Subset:  AIM; IM    
Affiliation:
Division of Cardiology, Niigata University Graduate School of Medical and Dental Sciences, Japan.
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MeSH Terms
Descriptor/Qualifier:
Animals
Autoimmune Diseases / therapy*
Cells / drug effects,  metabolism
Cytokines / genetics
Disease Models, Animal
Gene Expression Regulation / immunology
Gene Therapy / methods*
Immune System / drug effects
Immunoglobulins / administration & dosage*,  genetics,  therapeutic use
Interleukin 1 Receptor Antagonist Protein
Lymphocytes / drug effects,  metabolism
Male
Myocarditis / therapy*
Plasmids / administration & dosage*,  therapeutic use
Prostaglandin-Endoperoxide Synthases / genetics
Rats
Rats, Inbred Lew
Sialoglycoproteins / administration & dosage*,  genetics,  therapeutic use
Chemical
Reg. No./Substance:
0/Cytokines; 0/Immunoglobulins; 0/Interleukin 1 Receptor Antagonist Protein; 0/Sialoglycoproteins; EC 1.14.99.1/Prostaglandin-Endoperoxide Synthases

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