TY - JOUR AB - Nucleophosmin 1 (NPM1) primarily localizes to the nucleus and is passively released into the extracellular milieu by necrotic or damaged cells, or is secreted by monocytes and macrophages. Extracellular NPM1 acts as a potent inflammatory stimulator by promoting cytokine production [e.g., tumor necrosis factor‑α (TNF‑α)], which suggests that NPM1 acts as a damage‑associated molecular pattern. However, the receptor of NPM1 is unknown. Evidence indicates that DAMPs, which include high mobility group box 1 and histones, may bind Toll‑like receptors (TLRs). In the present study, it was shown that NPM1 signaling was mediated via the TLR4 pathway, which suggests that TLR4 is an NPM1 receptor. TLR4 binds myeloid differentiation protein‑2 (MD‑2), which is essential for intracellular signaling. Furthermore, the TLR4 antagonist, LPS‑Rhodobacter sphaeroides (an MD‑2 antagonist) and TAK‑242 (a TLR4 signaling inhibitor) significantly inhibited NPM1‑induced TNF‑α production by differentiated THP‑1 cells as well as reducing ERK1/2 activation. Far‑western blot analysis revealed that NPM1 directly bound MD‑2. Thus, the results of the present study provide compelling evidence that TLR4 binds NPM1, and it is hypothesized that inhibiting NPM1 activity may serve as a novel strategy for treating TLR4‑related diseases. AD - Department of Biomedical Engineering, Osaka Institute of Technology, Osaka 535‑8585, Japan Department of Pharmacology, Faculty of Dentistry, Mahidol University, Bangkok 10400, Thailand Veterinary Teaching Hospital, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890‑8580, Japan Department of Anesthesiology and Intensive Care Medicine, Tokyo Medical University, School of Medicine, Tokyo 160‑0023, Japan Suiyukai Clinic, Kashihara, Nara 634‑0007, Japan AU - Nakatomi,Kota AU - Ueno,Hikari AU - Ishikawa,Yuto AU - Salim,Ronny,Christiadi AU - Mori,Yuki AU - Kanemoto,Issey AU - Tancharoen,Salunya AU - Kikuchi,Kiyoshi AU - Miura,Naoki AU - Omori,Taketo AU - Okuda‑Ashitaka,Emiko AU - Matsumura,Kiyoshi AU - Imaizumi,Hitoshi AU - Motomiya,Yoshihiro AU - Maruyama,Ikuro AU - Kawahara,Ko-Ichi DA - 2021/02/01 DO - 10.3892/br.2020.1397 IS - 2 JO - Biomed Rep KW - damage‑associated molecular patterns myeloid differentiation protein‑2 nucleophosmin 1 Toll‑like receptor 4 sepsis PY - 2021 SN - 2049-9434 2049-9442 SP - 21 ST - TLR4/MD‑2 is a receptor for extracellular nucleophosmin 1 T2 - Biomedical Reports TI - TLR4/MD‑2 is a receptor for extracellular nucleophosmin 1 UR - https://doi.org/10.3892/br.2020.1397 VL - 14 ER -