Peroxisome proliferation-activated receptor-gamma ligands ameliorate experimental autoimmune myocarditis.
BACKGROUND
Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands have been shown to ameliorate a variety of inflammatory conditions. The present study tested the hypothesis that PPAR-gamma ligands reduce experimental autoimmune myocarditis (EAM) associated with inhibition of the expansion and activation of T cells, as well as suppression of the expression of proinflammatory cytokines.


RESULTS
EAM was induced in Lewis rats by immunization with porcine cardiac myosin. PPAR-gamma ligands, 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) 200 microg/kg/day i.p. and pioglitazone (PIO) 10 mg/kg/day orally, were administered for 3 weeks to rats with EAM. The results showed that enhanced PPAR-gamma expression was prominently stained in the nuclear and perinuclear regions of infiltrating inflammatory cells. Administration of PPAR-gamma ligands markedly reduced the severity of myocarditis, as shown by comparing the heart weight/body weight ratio, pericardial effusion scores, macroscopic scores and microscopic scores. PPAR-gamma ligands suppressed myocardial mRNA expression of inflammatory cytokines and the expression of interleukin (IL)-1beta protein in rats with EAM. In addition, 15d-PGJ(2) and PIO treatment suppressed the proliferative response and interferon-gamma production of T cell-enriched splenocytes from rats with EAM. Furthermore, the cytotoxic activity and myocardiogenic potential of these T cells were inhibited by 15d-PGJ(2) treatment.


CONCLUSIONS
PPAR-gamma may play a role in the pathophysiology of EAM. PPAR-gamma ligands ameliorate the EAM associated with suppression of the expansion and activation of myocardiogenic T cells, as well as inhibition of the expression of proinflammatory cytokines. These results suggest that PPAR-gamma ligands such as 15d-PGJ(2) and PIO may have the potential to modulate human inflammatory heart diseases such as myocarditis.
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007375:Interleukin-1 / Q000032:analysis / Q000378:metabolism; D023421:Models, Animal; D009205:Myocarditis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D000077205:Pioglitazone; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D018160:Receptors, Cytoplasmic and Nuclear / Q000032:analysis / Q000378:metabolism*; D045162:Thiazolidinediones / Q000627:therapeutic use*; D014157:Transcription Factors / Q000032:analysis / Q000378:metabolism*
C477819:15-deoxyprostaglandin J2; D007004:Hypoglycemic Agents; D007375:Interleukin-1; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D014157:Transcription Factors; D015230:Prostaglandin D2; D000077205:Pioglitazone