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.

Abstract

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
• Journal: Circulation (Circulation) Vol. 111 Issue 13 Pg. 1593-600 (Apr 05 2005) ISSN: 1524-4539 [Electronic] United States
• PMID: 15795329 (Publication Type: Journal Article)

Chemical References

• Cytokines
• Immunoglobulins
• Interleukin 1 Receptor Antagonist Protein
• Sialoglycoproteins
• Prostaglandin-Endoperoxide Synthases

Topics

• Animals
• Autoimmune Diseases (therapy)
• Cells (drug effects, metabolism)
• Cytokines (genetics)
• Disease Models, Animal
• Gene Expression Regulation (immunology)
• Genetic 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)