Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sepsis results in a profound state of immunosuppression, which is temporally associated with impaired leukocyte function. The mechanism of leukocyte reprogramming in sepsis is incompletely understood. In this study, we explored mechanisms contributing to dysregulated inflammatory cytokine expression by pulmonary macrophages during experimental sepsis. Pulmonary macrophages (PM) recovered from the lungs of mice undergoing cecal ligation and puncture (CLP) display transiently reduced expression of some, but not all innate genes in response to LPS. Impaired expression of TNF-alpha and iNOS was associated with reduced acetylation and methylation of specific histones (AcH4 and H3K4me3) and reduced binding of RNA polymerase II to the promoters of these genes. Transient impairment in LPS-induced cytokine responses in septic PM temporally correlated with induction of IRAK-M mRNA and protein, which occurred in a MyD88-dependent fashion. PM isolated from IRAK-M(-/-) mice were largely refractory to CLP-induced impairment in cytokine expression, chromatin remodeling, recruitment of RNA polymerase II, and induction of histone deacetylase-2 observed during sepsis. Our findings indicate that systemic sepsis induces epigenetic silencing of cytokine gene expression in lung macrophages, and IRAK-M appears to be a critical mediator of this response.
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PMID:IRAK-M regulates chromatin remodeling in lung macrophages during experimental sepsis. 2058 89

In the current study, we present an innovative concept based on the knowledge that enhancing naturally occurring biological mechanisms is effective in preventing neuronal damage and maintaining low disease activity in about 15% of multiple sclerosis (MS) patients presenting the benign type of MS. Recently, we have demonstrated that low disease activity in benign MS is associated with suppression of RNA polymerase 1 (POL1) pathway; therefore, targeting POL1 transcription machinery as a strategy for suppressing active forms of MS is suggested. To further establish our approach, we aimed to suppress POL1 pathway by silencing of the POL1-related RRN3, POLR1D and LRPPRC genes in specific MOG35-55-activated lymphocytes and assess their capacity to induce experimental autoimmune encephalomyelitis (EAE) by passive transfer. We have demonstrated that silencing of specific POL1 pathway-related genes significantly decreased viability and increased the proportion of CD4+/AnnexinV+/PI+ apoptotic cells in MOG35-55-primed lymphocytes. POL1-gene silencing significantly decreased the proportion of CD4+IL17+ and increased proportion of CD4+IL10+ and CD4+TNFa+ lymphocytes that occurred simultaneously with over-presentation of Treg CD4+CD25+FoxP3+ cells. Passive transfer of MOG35-55-primed lymphocytes after POL1-gene silencing suppressed EAE development in mice as demonstrated by delayed onset and peak of disease accompanied by significantly lower maximal and cumulative EAE scores. Our study supports a basis for direct targeting of POL1 transcription pathway as a strategy for selective induction of apoptosis and suppression of inflammation in EAE and consequently paves the way for innovative and targeted MS therapeutic strategy that is based on naturally existing biological mechanism.
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PMID:Experimental Autoimmune Encephalomyelitis Ameliorated by Passive Transfer of Polymerase 1-Silenced MOG35-55 Lymphatic Node Cells: Verification of a Novel Therapeutic Approach in Multiple Sclerosis. 2875 38


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