التفاصيل البيبلوغرافية
| العنوان: |
Regulation of NF-κB Circuitry by a Component of the Nucleosome Remodeling and Deacetylase Complex Controls Inflammatory Response Homeostasis. |
| المؤلفون: |
Pakala, Suresh B.1, Bui-Nguyen, Tri M., Reddy, Sirigiri Divijendra Natha, Li, Da-Qiang2, Peng, Shaohua3, Rayala, Suresh K.3, Behringer, Richard R.4, Kumar, Rakesh2,3 bcmrxk@gwumc.edu |
| المصدر: |
Journal of Biological Chemistry. 7/30/2010, Vol. 285 Issue 31, p23590-23597. 8p. 7 Diagrams. |
| مصطلحات موضوعية: |
*TUMOR antigens, *CANCER, *ESCHERICHIA coli, *ENDOTOXINS, *MACROPHAGES, *CYTOKINES |
| مستخلص: |
The MTA1 coregulator (metastatic tumor antigen 1), a component of the nucleosome remodeling and deacetylase (NuRD) complex, has been intimately linked with human cancer, but its role in inflammatory responses remains unknown. Here, we discovered that MTAI is a target of inflammation, and stimulation of macrophages with Escherichia coli lipopolysaccharide (LPS) stimulates MTA1 transcription via the NF-ΚB pathway. Unexpectedly, we found that MTA1 depletion in LPS-stimulated macrophages impairs NF-ΚB signaling and expression of inflammatory molecules. MTA1 itself acts as a transcriptional coactivator of inflammatory cytokines in LPS-stimulated macrophages, and in contrast, it acts as a corepressor in resting primary macrophages as its depletion induced cytokine expression. LPS stimulates S-nitrosylation of histone deacetylase 2 (HDAC2) and interferes with its binding to MTA1, which, in turn, resulted in the loss of corepressor behavior of MTA1 x HDAC complex in activated macrophages. Consequently, the net levels of inflammatory cytokines in LPSstimulated macrophages from MTA1-/- mice were high compared with wild-type mice. Accordingly, MTA1-/- mice were much more susceptible than control mice to septic shock induced by LPS, revealing that MTA1 protects mice from deregulated host inflammatory response. These findings reveal a previously unrecognized, critical homeostatic role of MTA1, both as a target and as a component of the NF-ΚB circuitry, in the regulation of inflammatory responses. [ABSTRACT FROM AUTHOR] |
| قاعدة البيانات: |
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