Local expression of interleukin-1 receptor antagonist by plasmid DNA improves mortality and decreases myocardial inflammation in experimental coxsackieviral myocarditis.
BACKGROUND
The inflammatory cytokines have an important role in the pathogenesis of viral myocarditis. Inerleukin-1 (IL-1) is one of the major cytokines that modulate the outcome of viral infection. Among the methods for in vivo gene transfer, direct injection of plasmid DNA is one that is simple and feasible. In this study, we expressed human IL-1 receptor antagonist (hIL-1Ra) in the mouse heart by direct injection of a novel plasmid vector and evaluated its effects on coxsackieviral (CVB3) myocarditis.


RESULTS
A plasmid vector expressing hIL-1Ra (total 40 microg/mouse) was injected into the heart apex of 8-week-old inbred female Balb/C mice (day 3). On day 0, mice (IL-1Ra-CVB3, n=35) were infected intraperitoneally with 10(4) PFU of CVB3; control mice (pCK-CVB3, n=15) were injected with empty vector on day -3 and infected on day 0. hIL-1Ra was expressed in the heart, reached its peak on day 5, and persisted for 2 weeks. The 14-day survival rate of IL-1Ra-CVB3 was higher (77%) than that of controls (30%, P<0.01). Myocardial virus titers on day 3 were lower in IL-1Ra-CVB3 mice. Myocardial inflammation on day 7 and fibrosis on day 14 were markedly decreased in IL-1Ra-CVB3.


CONCLUSIONS
These results showed that direct injection of the expression plasmid vector into the heart was an effective method to transfer the cytokine gene in vivo, and expressed IL-1Ra in the heart can modulate the deleterious effect of the host immune response in viral myocarditis.
Lim
Byung-Kwan
BK
Department of Medicine, Cardiovascular Institute, Samsung Medical Center, Seoul, South Korea.
Choe
Seong-Choon
SC
Shin
Jae-Ok
JO
Ho
Seong-Hyun
SH
Kim
Jong-Mook
JM
Yu
Seung-Shin
SS
Kim
Sunyoung
S
Jeon
Eun-Seok
ES
D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D004333:Drug Administration Routes; D029822:Enterovirus B, Human / Q000472:pathogenicity; D005260:Female; D005355:Fibrosis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D015316:Genetic Therapy / Q000379:methods*; D006321:Heart / Q000821:virology; D006801:Humans; D007267:Injections; D053590:Interleukin 1 Receptor Antagonist Protein; D051379:Mice; D008807:Mice, Inbred BALB C; D009205:Myocarditis / Q000150:complications / Q000473:pathology / Q000628:therapy* / Q000821:virology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010957:Plasmids / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D012795:Sialoglycoproteins / Q000008:administration & dosage* / Q000096:biosynthesis* / Q000235:genetics; D015996:Survival Rate; D016896:Treatment Outcome; D010948:Viral Plaque Assay
C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D012795:Sialoglycoproteins