Interleukin-12 receptor/STAT4 signaling is required for the development of autoimmune myocarditis in mice by an interferon-gamma-independent pathway.
BACKGROUND
Interleukin (IL)-12 exerts a potent proinflammatory effect by stimulating T-helper (Th) 1 responses. This effect is believed to be mediated primarily through the activation of STAT4 and subsequent production of interferon (IFN)-gamma. Methods and Results- We examined the role of IL-12 receptor (IL-12R) signaling in the development of murine experimental autoimmune myocarditis (EAM) induced by cardiac myosin immunization. Both IL-12Rbeta1-deficient mice and STAT4-deficient mice were resistant to the induction of myocarditis. Treatment with exogenous IL-12 exacerbated disease. We questioned whether IFN-gamma is required for the disease-promoting activity of IL-12. On the contrary, we found that IFN-gamma suppresses EAM. Lack of IFN-gamma due to either depletion with an antibody or a genetic deficiency exacerbated myocarditis. Spleens from IFN-gamma-deficient mice immunized with cardiac myosin showed increased cellularity; greater numbers of CD3+, CD4+, CD8+, and IL-2-producing cells; and heightened ability to produce cytokines on stimulation in vitro. Treatment of mice with recombinant IFN-gamma suppressed the development of myocarditis.


CONCLUSIONS
IL-12/IL-12R/STAT4 signaling promotes the development of EAM. In contrast, IFN-gamma plays a protective role. The disease-limiting effects of IFN-gamma might be explained by its ability to control the expansion of activated T lymphocytes.
Afanasyeva
M
M
Department of Pathology, W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Medical Institutions, Baltimore, Md, USA.
Wang
Y
Y
Kaya
Z
Z
Stafford
E A
EA
Dohmen
K M
KM
Sadighi Akha
A A
AA
Rose
N R
NR
D000818:Animals; D001327:Autoimmune Diseases / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D017252:CD3 Complex / Q000032:analysis; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D002478:Cells, Cultured; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D005838:Genotype; D007371:Interferon-gamma / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D018664:Interleukin-12 / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009205:Myocarditis / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D009206:Myocardium / Q000276:immunology / Q000473:pathology; D009218:Myosins / Q000276:immunology; D018123:Receptors, Interleukin / Q000235:genetics / Q000502:physiology*; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*
D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D016207:Cytokines; D004268:DNA-Binding Proteins; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D015534:Trans-Activators; D018664:Interleukin-12; D007371:Interferon-gamma; D009218:Myosins