title: 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).
  
  
  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.affiliation: Division of Cardiology, Niigata University Graduate School of Medical and Dental Sciences, Japan.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.forename: Haruo
authors.initials: H
authors.lastname: Hanawa
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Raafat
authors.initials: R
authors.lastname: Elnaggar
authors.forename: Manabu
authors.initials: M
authors.lastname: Hayashi
authors.forename: Ritsuo
authors.initials: R
authors.lastname: Watanabe
authors.forename: Ken
authors.initials: K
authors.lastname: Toba
authors.forename: Kaori
authors.initials: K
authors.lastname: Yoshida
authors.forename: He
authors.initials: H
authors.lastname: Chang
authors.forename: Yuji
authors.initials: Y
authors.lastname: Okura
authors.forename: Kiminori
authors.initials: K
authors.lastname: Kato
authors.forename: Makoto
authors.initials: M
authors.lastname: Kodama
authors.forename: Hiroki
authors.initials: H
authors.lastname: Maruyama
authors.forename: Junichi
authors.initials: J
authors.lastname: Miyazaki
authors.forename: Mikio
authors.initials: M
authors.lastname: Nakazawa
authors.forename: Yoshifusa
authors.initials: Y
authors.lastname: Aizawa
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000628:therapy*; D002477:Cells / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000276:immunology; D015316:Genetic Therapy / Q000379:methods*; D007107:Immune System / Q000187:drug effects; D007136:Immunoglobulins / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D053590:Interleukin 1 Receptor Antagonist Protein; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009205:Myocarditis / Q000628:therapy*; D010957:Plasmids / Q000008:administration & dosage* / Q000627:therapeutic use; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D051381:Rats; D011917:Rats, Inbred Lew; D012795:Sialoglycoproteins / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use
chemical_list: D016207:Cytokines; D007136:Immunoglobulins; D053590:Interleukin 1 Receptor Antagonist Protein; D012795:Sialoglycoproteins; D011451:Prostaglandin-Endoperoxide Synthases