Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Th1-type immune responses, mediated by IL-12-induced IFN-gamma, are believed to exacerbate certain autoimmune diseases. We recently found that signaling via IL-12Rbeta1 increases coxsackievirus B3 (CVB3)-induced myocarditis. In this study, we examined the role of IL-12 on the development of CVB3-induced myocarditis using mice deficient in IL-12p35 that lack IL-12p70. We found that IL-12 deficiency did not prevent myocarditis, but viral replication was significantly increased. Although there were no changes in the total percentage of inflammatory cells in IL-12-deficient hearts compared with wild-type BALB/c controls by FACS analysis, macrophage and neutrophil populations were decreased. This decrease corresponded to reduced TNF-alpha and IFN-gamma levels in the heart, suggesting that macrophage and/or neutrophil populations may be a primary source of TNF-alpha and IFN-gamma during acute CVB3 myocarditis. Increased viral replication in IL-12-deficient mice was not mediated by reduced TNFRp55 signaling, because viral replication was unaltered in TNFRp55-deficient mice. However, STAT4 or IFN-gamma deficiency resulted in significantly increased viral replication and significantly reduced TNF-alpha and IFN-gamma levels in the heart, similar to IL-12 deficiency, indicating that the IL-12/STAT4 pathway of IFN-gamma production is important in limiting CVB3 replication. Furthermore, STAT4 or IFN-gamma deficiency also increased chronic CVB3 myocarditis, indicating that therapeutic strategies aimed at reducing Th1-mediated autoimmune diseases may exacerbate common viral infections such as CVB3 and increase chronic inflammatory heart disease.
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PMID:IL-12 protects against coxsackievirus B3-induced myocarditis by increasing IFN-gamma and macrophage and neutrophil populations in the heart. 1561 Dec 48

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.
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PMID:Sex differences in coxsackievirus B3-induced myocarditis: IL-12Rbeta1 signaling and IFN-gamma increase inflammation in males independent from STAT4. 1694 58

Heart failure (HF) is the end stage of most heart disease cases and can be initiated from multiple aetiologies. However, whether the molecular basis of HF has a commonality between different aetiologies has not been elucidated. To address this lack, we performed a three-tiered analysis by integrating transcriptional data and pathway information to explore the commonalities of HF from different aetiologies. First, through differential expression analysis, we obtained 111 genes that were frequently differentially expressed in HF from 11 different aetiologies. Several genes, such as NPPA and NPPB, are early and accurate biomarkers for HF. We also provided candidates for further experimental verification, such as SERPINA3 and STAT4. Then, using gene set enrichment analysis, we successfully identified 19 frequently dysregulated pathways. In particular, we found that pathways related to immune system signalling, the extracellular matrix and metabolism were critical in the development of HF. Finally, we successfully acquired 241 regulatory relationships between 64 transcriptional factors (TFs) and 17 frequently dysregulated pathways by integrating a regulatory network, and some of the identified TFs have already been proven to play important roles in HF. Taken together, the three-tiered analysis of HF provided a systems biology perspective on HF and emphasized the molecular commonality of HF from different aetiologies.
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PMID:A three-tiered integrative analysis of transcriptional data reveals the shared pathways related to heart failure from different aetiologies. 3263 46