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1.
J Am Heart Assoc ; 8(2): e008968, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30638108

RESUMO

Background Myocarditis is an important cause of acute and chronic heart failure. Men with myocarditis have worse recovery and an increased need for transplantation compared with women, but the reason for the sex difference remains unclear. Elevated sera soluble (s) ST2 predicts mortality from acute and chronic heart failure, but has not been studied in myocarditis patients. Methods and Results Adults with a diagnosis of clinically suspected myocarditis (n=303, 78% male) were identified according to the 2013 European Society of Cardiology position statement. Sera sST2 levels were examined by ELISA in humans and mice and correlated with heart function according to sex and age. Sera sST2 levels were higher in healthy men ( P=8×10-6) and men with myocarditis ( P=0.004) compared with women. sST2 levels were elevated in patients with myocarditis and New York Heart Association class III - IV heart failure ( P=0.002), predominantly in men ( P=0.0003). Sera sST2 levels were associated with New York Heart Association class in men with myocarditis who were ≤50 years old ( r=0.231, P=0.0006), but not in women ( r=0.172, P=0.57). Sera sST2 levels were also significantly higher in male mice with myocarditis ( P=0.005) where levels were associated with cardiac inflammation. Gonadectomy with hormone replacement showed that testosterone ( P<0.001), but not estradiol ( P=0.32), increased sera sST2 levels in male mice with myocarditis. Conclusions We show in a well-characterized subset of heart failure patients with clinically suspected and biopsy-confirmed myocarditis that elevated sera sST2 is associated with an increased risk of heart failure based on New York Heart Association class in men ≤50 years old.

2.
Am J Physiol Regul Integr Comp Physiol ; 304(4): R267-77, 2013 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-23255589

RESUMO

Recent findings indicate that TLR3 polymorphisms increase susceptibility to enteroviral myocarditis and inflammatory dilated cardiomyopathy (iDCM) in patients. TLR3 signaling has been found to inhibit coxsackievirus B3 (CVB3) replication and acute myocarditis in mouse models, but its role in the progression from myocarditis to iDCM has not been previously investigated. In this study we found that TLR3 deficiency increased acute (P = 5.9 × 10(-9)) and chronic (P = 6.0 × 10(-7)) myocarditis compared with WT B6.129, a mouse strain that is resistant to chronic myocarditis and iDCM. Using left ventricular in vivo hemodynamic assessment, we found that TLR3-deficient mice developed progressively worse chronic cardiomyopathy. TLR3 deficiency significantly increased viral replication in the heart during acute myocarditis from day 3 through day 12 after infection, but infectious virus was not detected in the heart during chronic disease. TLR3 deficiency increased cytokines associated with a T helper (Th)2 response, including IL-4 (P = 0.03), IL-10 (P = 0.008), IL-13 (P = 0.002), and TGF-ß(1) (P = 0.005), and induced a shift to an immunoregulatory phenotype in the heart. However, IL-4-deficient mice had improved heart function during acute CVB3 myocarditis by echocardiography and in vivo hemodynamic assessment compared with wild-type mice, indicating that IL-4 impairs cardiac function during myocarditis. IL-4 deficiency increased regulatory T-cell and macrophage populations, including FoxP3(+) T cells (P = 0.005) and Tim-3(+) macrophages (P = 0.004). Thus, TLR3 prevents the progression from myocarditis to iDCM following CVB3 infection by reducing acute viral replication and IL-4 levels in the heart.


Assuntos
Cardiomiopatia Dilatada/virologia , Infecções por Coxsackievirus/imunologia , Enterovirus Humano B/fisiologia , Interleucina-4/imunologia , Miocardite/virologia , Receptor 3 Toll-Like/imunologia , Doença Aguda , Animais , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/imunologia , Doença Crônica , Infecções por Coxsackievirus/genética , Citocinas/biossíntese , Citocinas/imunologia , Modelos Animais de Doenças , Humanos , Interleucina-4/análise , Macrófagos/imunologia , Macrófagos/virologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Miocardite/genética , Miocardite/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/virologia , Receptor 3 Toll-Like/genética , Replicação Viral/imunologia
3.
Brain Behav Immun ; 23(5): 649-57, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19126426

RESUMO

The incidence of cardiovascular disease, including inflammatory heart diseases like myocarditis, is increased in men. Similarly, male BALB/c mice infected with coxsackievirus B3 (CVB3) develop more severe acute inflammation in the heart compared to females. To better understand the effect of male sex hormones on cardiac inflammation, we gonadectomized (Gdx) male BALB/c mice and examined acute CVB3-induced myocarditis compared to sham controls. Viral replication in the heart was not significantly altered between Gdx and sham mice. However, gonadectomy significantly reduced testosterone levels and inflammation in the heart. FACS analysis of cell populations isolated from the heart revealed that CD11b(+) cells were significantly reduced in Gdx males. However, a GR1(+)F4/80(+) subset of CD11b(+) cells was significantly increased. Because this subset also expressed the interleukin (IL)-4R and IL-10, we refer to these cells as "alternatively activated" or M2 macrophages. A greater percentage of M2 macrophages in Gdx males expressed the inhibitory receptor Tim-3, while fewer expressed IL-1beta and IL-10. Only M2 macrophages upregulated TLR4 and Tim-3, whereas GR1(-)IL-4R(lo) macrophages did not. Additionally, IL-4(+)CD4(+) Th2 cells, Foxp3(+) regulatory T (Treg) cells and Tim-3(+)CD4(+) T cells were significantly increased in the heart following Gdx. Thus, we report for the first time that the inhibitory receptor Tim-3 is expressed on M2 macrophages. Our findings show that sex hormones and/or other mediators released from the testes inhibit anti-inflammatory populations in the heart including Tim-3(+) M2, Tim-3(+)CD4(+) T cells, Th2 and Treg resulting in more severe acute cardiac inflammation in males following CVB3 infection.


Assuntos
Infecções por Coxsackievirus/imunologia , Ativação de Macrófagos , Miocardite/imunologia , Orquiectomia , Linfócitos T Reguladores/imunologia , Células Th2/imunologia , Doença Aguda , Animais , Antígeno CD11b/análise , Infecções por Coxsackievirus/sangue , Infecções por Coxsackievirus/fisiopatologia , Citocinas/sangue , Enterovirus Humano B/fisiologia , Receptor Celular 2 do Vírus da Hepatite A , Antígenos Comuns de Leucócito/análise , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Miocardite/sangue , Miocardite/fisiopatologia , Miocárdio/imunologia , Receptores Virais/análise , Testosterona/sangue , Replicação Viral
4.
J Immunol ; 178(11): 6710-4, 2007 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-17513715

RESUMO

Recent clinical studies have reinforced the importance of sex-related differences in the pathogenesis of cardiovascular diseases, with an increased incidence and mortality in men. Similar to humans, male BALB/c mice infected with coxsackievirus B3 (CVB3) develop more severe inflammation in the heart even though viral replication is no greater than in females. We show that TLR4 and IFN-gamma levels are significantly elevated and regulatory T cell (Treg) populations significantly reduced in the heart of males following CVB3 infection, whereas females have significantly increased T cell Ig mucin (Tim)-3, IL-4 and Treg. Blocking Tim-3 in males significantly increases inflammation and TLR4 expression while reducing Treg. In contrast, defective TLR4 signaling significantly reduces inflammation while increasing Tim-3 expression. Cross-regulation of TLR4 and Tim-3 occurs during the innate and adaptive immune response. This novel mechanism may help explain why inflammatory heart disease is more severe in males.


Assuntos
Miocardite/imunologia , Miocardite/fisiopatologia , Receptor Cross-Talk/imunologia , Receptores Virais/fisiologia , Caracteres Sexuais , Receptor 4 Toll-Like/fisiologia , Animais , Infecções por Coxsackievirus/imunologia , Infecções por Coxsackievirus/metabolismo , Infecções por Coxsackievirus/fisiopatologia , Enterovirus Humano B/imunologia , Feminino , Receptor Celular 2 do Vírus da Hepatite A , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Mastócitos/imunologia , Mastócitos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Camundongos Transgênicos , Miocardite/metabolismo , Miocardite/virologia , Receptores Virais/antagonistas & inibidores , Receptores Virais/biossíntese , Transdução de Sinais/imunologia , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/biossíntese , Regulação para Cima/imunologia
5.
Brain Res ; 1126(1): 139-47, 2006 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-16949558

RESUMO

Cardiovascular disease is the number one killer of men and women in North America. Male BALB/c mice infected with coxsackievirus B3 (CVB3) develop more severe inflammatory heart disease compared to female mice, similar to the increased heart disease that occurs in men. We show here that increased inflammation in male mice is not due to increased viral replication in the heart, but associated with increased proinflammatory cytokines IL-1beta, IL-18 and IFN-gamma. We have previously reported that IL-12Rbeta1 signaling increases CVB3-induced myocarditis and IL-1beta/IL-18 levels in males, while IL-12(p35)/STAT4-induced IFN-gamma does not alter the severity of acute disease. However, whether differences exist between males and females in these two cytokine signaling pathways is unknown. In this study, we examined sex differences in 1) IL-12Rbeta1 signaling or 2) STAT4/IFN-gamma pathways following CVB3 infection in BALB/c mice. We found that male and female mice deficient in IL-12Rbeta1 had decreased inflammation and viral replication in the heart, indicating that IL-12Rbeta1 signaling increases myocarditis in both sexes. In contrast, STAT4 deficiency did not alter the sex difference in myocarditis, with males maintaining increased inflammation over females. IFN-gamma deficient males, however, had decreased myocarditis and viral replication compared to females. Thus, IFN-gamma increases inflammation in males independent from STAT4. These results demonstrate that sex differences greatly influence viral replication and the severity of acute CVB3-induced myocarditis.


Assuntos
Interferon gama/genética , Miocardite/genética , Miocardite/imunologia , Receptores de Interleucina-12/genética , Fator de Transcrição STAT4/genética , Caracteres Sexuais , Animais , Infecções por Coxsackievirus/genética , Infecções por Coxsackievirus/imunologia , Modelos Animais de Doenças , Progressão da Doença , Enterovirus/imunologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Miocardite/virologia , Miocárdio/imunologia , Miocárdio/patologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Replicação Viral/genética , Replicação Viral/imunologia
6.
J Immunol ; 176(6): 3516-24, 2006 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-16517720

RESUMO

Complement and complement receptors (CR) play a central role in immune defense by initiating the rapid destruction of invading microorganisms, amplifying the innate and adaptive immune responses, and mediating solubilization and clearance of immune complexes. Defects in the expression of C or CR have been associated with loss of tolerance to self proteins and the development of immune complex-mediated autoimmune diseases such as systemic lupus erythematosus. In this study, we examined the role of CR on coxsackievirus B3 (CVB3)-induced myocarditis using mice deficient in CR1/2. We found that CR1/2 deficiency significantly increased acute CVB3 myocarditis and pericardial fibrosis resulting in early progression to dilated cardiomyopathy and heart failure. The increase in inflammation was not due to increased viral replication, which was not significantly altered in the hearts of CR1/2-deficient mice, but was associated with increased numbers of macrophages, IL-1beta levels, and immune complex deposition in the heart. The complement regulatory protein, CR1-related gene/protein Y (Crry), was increased on cardiac macrophage populations, while immature B220(low) B cells were increased in the spleen of CR1/2-deficient mice during acute CVB3-induced myocarditis. These results show that expression of CR1/2 is not necessary for effective clearance of CVB3 infection, but prevents immune-mediated damage to the heart.


Assuntos
Enterovirus/fisiologia , Coração/fisiopatologia , Interleucina-1/biossíntese , Macrófagos/imunologia , Miocardite/fisiopatologia , Miocardite/virologia , Receptores de Complemento/metabolismo , Animais , Linfócitos B/citologia , Linfócitos B/virologia , Proliferação de Células , Células Cultivadas , Fibrose/metabolismo , Fibrose/patologia , Interleucina-1/imunologia , Macrófagos/citologia , Masculino , Camundongos , Camundongos Knockout , Miocardite/imunologia , Miocardite/patologia , Receptores de Complemento/deficiência , Receptores de Complemento/genética , Baço/citologia , Baço/virologia , Linfócitos T/citologia , Fator de Necrose Tumoral alfa/biossíntese
7.
Cancer Res ; 63(19): 6424-31, 2003 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-14559832

RESUMO

We have previously shown a critical role for IFN regulatory factor 5 (IRF-5) in the innate immune response to virus infection. For the first time, we now show that although IRF-5 is a direct target of p53, its cell cycle regulatory and proapoptotic effects are p53 independent. IRF-5 inhibits both in vitro and in vivo B-cell lymphoma tumor growth in the absence of wild-type p53. The molecular mechanism(s) of IRF-5-mediated growth inhibition is associated with a G(2)-M cell cycle arrest and modulation of growth regulatory and proapoptotic genes, including p21, Bak, DAP kinase 2, and Bax. Taken together, these data indicate that although IRF-5 is a downstream target of p53, its growth inhibitory and proapoptotic effects are independent of p53.


Assuntos
Apoptose/fisiologia , Ciclo Celular/fisiologia , Proteínas de Ligação a DNA/fisiologia , Proteínas Proto-Oncogênicas c-bcl-2 , Fatores de Transcrição/fisiologia , Animais , Caspase 8 , Caspase 9 , Caspases/biossíntese , Caspases/genética , Divisão Celular/fisiologia , Inibidor de Quinase Dependente de Ciclina p21 , Ciclinas/biossíntese , Ciclinas/genética , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/genética , Feminino , Fase G2/fisiologia , Células HCT116 , Humanos , Fator Regulador 7 de Interferon , Fatores Reguladores de Interferon , Leucemia/genética , Leucemia/metabolismo , Leucemia/patologia , Leucócitos Mononucleares/metabolismo , Linfoma de Células B/genética , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Camundongos , Camundongos Nus , Mitose/fisiologia , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/genética , Transdução de Sinais/fisiologia , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética , Proteína Supressora de Tumor p53/fisiologia , Proteína Killer-Antagonista Homóloga a bcl-2 , Proteína X Associada a bcl-2
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