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https://hdl.handle.net/2440/87715
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Type: | Journal article |
Title: | Rifampin inhibits Toll-like receptor 4 signaling by targeting myeloid differentiation protein 2 and attenuates neuropathic pain |
Author: | Wang, X. Grace, P. Pham, M. Cheng, K. Strand, K. Smith, C. Li, J. Watkins, L. Yin, H. |
Citation: | The FASEB Journal, 2013; 27(7):2713-2722 |
Publisher: | Federation of American Societies for Experimental Biology |
Issue Date: | 2013 |
ISSN: | 0892-6638 1530-6860 |
Statement of Responsibility: | Xiaohui Wang, Peter M. Grace, Michael N. Pham, Kui Cheng, Keith A. Strand, Christina Smith, Jing Li, Linda R. Watkins, and Hang Yin |
Abstract: | Rifampin has been used for the treatment of bacterial infections for many years. Clinically, rifampin has been found to possess immunomodulatory effects. However, the molecular target responsible for the immunosuppressive effects of rifampin is not known. Herein, we show that rifampin binds to myeloid differentiation protein 2 (MD-2), the key coreceptor for innate immune TLR4. Rifampin blocked TLR4 signaling induced by LPS, including NF-κB activation and the overproduction of proinflammatory mediators nitric oxide, interleukin 1β, and tumor necrosis factor α in mouse microglia BV-2 cells and macrophage RAW 264.7 cells. Rifampin's inhibition of TLR4 signaling was also observed in immunocompetent rat primary macrophage, microglia, and astrocytes. Further, we show that rifampin (75 or 100 mg/kg b.i.d. for 3 d, intraperitoneal) suppressed allodynia induced by chronic constriction injury of the sciatic nerve and suppressed nerve injury-induced activation of microglia. Our findings indicate that MD-2 is a important target of rifampin in its inhibition of innate immune function and contributes to its clinically observed immune-suppressive effect. The results also suggest that rifampin may be repositioned as an agent for the treatment of neuropathic pain.—Wang, X., Grace, P. M., Pham, M. N., Cheng, K., Strand, K. A., Smith, C., Li, J., Watkins, L. R., Yin, H. Rifampin inhibits Toll-like receptor 4 signaling by targeting myeloid differentiation protein 2 and attenuates neuropathic pain. |
Keywords: | Microglia Cells, Cultured Cell Line Macrophages Animals Animals, Newborn Humans Mice Rats Rats, Sprague-Dawley Neuralgia Hyperalgesia Nitric Oxide Rifampin Tumor Necrosis Factor-alpha NF-kappa B Blotting, Western Signal Transduction Protein Binding Dose-Response Relationship, Drug Male Toll-Like Receptor 4 Lymphocyte Antigen 96 Interleukin-1beta HEK293 Cells |
Rights: | © FASEB |
DOI: | 10.1096/fj.12-222992 |
Published version: | http://dx.doi.org/10.1096/fj.12-222992 |
Appears in Collections: | Aurora harvest 7 Medicine publications |
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