title: Rifampin inhibits Toll-like receptor 4 signaling by targeting myeloid differentiation protein 2 and attenuates neuropathic pain.
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.
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, CO 80309, USA.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Wang
authors.forename: Peter M
authors.initials: PM
authors.lastname: Grace
authors.forename: Michael N
authors.initials: MN
authors.lastname: Pham
authors.forename: Kui
authors.initials: K
authors.lastname: Cheng
authors.forename: Keith A
authors.initials: KA
authors.lastname: Strand
authors.forename: Christina
authors.initials: C
authors.lastname: Smith
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Linda R
authors.initials: LR
authors.lastname: Watkins
authors.forename: Hang
authors.initials: H
authors.lastname: Yin
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D006930:Hyperalgesia / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D053583:Interleukin-1beta / Q000378:metabolism; D051218:Lymphocyte Antigen 96 / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009437:Neuralgia / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D009569:Nitric Oxide / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D012293:Rifampin / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D051218:Lymphocyte Antigen 96; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D012293:Rifampin
keywords: drug repositioning; inflammation; innate immune; microglia