Gedunin Binds to Myeloid Differentiation Protein 2 and Impairs Lipopolysaccharide-Induced Toll-Like Receptor 4 Signaling in Macrophages.

Autor:	Borges PV; Laboratory of Applied Pharmacology, Institute of Drug Technology (P.V.B., K.H.M., P.P., M.d.G.H., C.P.), Computational Science Program, Computational Biophysics and Molecular Modeling Group (P.R.B.; E.R.C.), and Center for Technological Development in Health (M.G.H., C.P.), Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; and Laborator of Immunopharmacology (C.M.M.-M.) and Molecular Biology and Endemic Diseases (F.S.S., C.R.A.), Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil., Moret KH; Laboratory of Applied Pharmacology, Institute of Drug Technology (P.V.B., K.H.M., P.P., M.d.G.H., C.P.), Computational Science Program, Computational Biophysics and Molecular Modeling Group (P.R.B.; E.R.C.), and Center for Technological Development in Health (M.G.H., C.P.), Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; and Laborator of Immunopharmacology (C.M.M.-M.) and Molecular Biology and Endemic Diseases (F.S.S., C.R.A.), Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil., Maya-Monteiro CM; Laboratory of Applied Pharmacology, Institute of Drug Technology (P.V.B., K.H.M., P.P., M.d.G.H., C.P.), Computational Science Program, Computational Biophysics and Molecular Modeling Group (P.R.B.; E.R.C.), and Center for Technological Development in Health (M.G.H., C.P.), Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; and Laborator of Immunopharmacology (C.M.M.-M.) and Molecular Biology and Endemic Diseases (F.S.S., C.R.A.), Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil., Souza-Silva F; Laboratory of Applied Pharmacology, Institute of Drug Technology (P.V.B., K.H.M., P.P., M.d.G.H., C.P.), Computational Science Program, Computational Biophysics and Molecular Modeling Group (P.R.B.; E.R.C.), and Center for Technological Development in Health (M.G.H., C.P.), Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; and Laborator of Immunopharmacology (C.M.M.-M.) and Molecular Biology and Endemic Diseases (F.S.S., C.R.A.), Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil., Alves CR; Laboratory of Applied Pharmacology, Institute of Drug Technology (P.V.B., K.H.M., P.P., M.d.G.H., C.P.), Computational Science Program, Computational Biophysics and Molecular Modeling Group (P.R.B.; E.R.C.), and Center for Technological Development in Health (M.G.H., C.P.), Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; and Laborator of Immunopharmacology (C.M.M.-M.) and Molecular Biology and Endemic Diseases (F.S.S., C.R.A.), Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil., Batista PR; Laboratory of Applied Pharmacology, Institute of Drug Technology (P.V.B., K.H.M., P.P., M.d.G.H., C.P.), Computational Science Program, Computational Biophysics and Molecular Modeling Group (P.R.B.; E.R.C.), and Center for Technological Development in Health (M.G.H., C.P.), Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; and Laborator of Immunopharmacology (C.M.M.-M.) and Molecular Biology and Endemic Diseases (F.S.S., C.R.A.), Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil., Caffarena ER; Laboratory of Applied Pharmacology, Institute of Drug Technology (P.V.B., K.H.M., P.P., M.d.G.H., C.P.), Computational Science Program, Computational Biophysics and Molecular Modeling Group (P.R.B.; E.R.C.), and Center for Technological Development in Health (M.G.H., C.P.), Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; and Laborator of Immunopharmacology (C.M.M.-M.) and Molecular Biology and Endemic Diseases (F.S.S., C.R.A.), Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil., Pacheco P; Laboratory of Applied Pharmacology, Institute of Drug Technology (P.V.B., K.H.M., P.P., M.d.G.H., C.P.), Computational Science Program, Computational Biophysics and Molecular Modeling Group (P.R.B.; E.R.C.), and Center for Technological Development in Health (M.G.H., C.P.), Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; and Laborator of Immunopharmacology (C.M.M.-M.) and Molecular Biology and Endemic Diseases (F.S.S., C.R.A.), Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil., Henriques Md; Laboratory of Applied Pharmacology, Institute of Drug Technology (P.V.B., K.H.M., P.P., M.d.G.H., C.P.), Computational Science Program, Computational Biophysics and Molecular Modeling Group (P.R.B.; E.R.C.), and Center for Technological Development in Health (M.G.H., C.P.), Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; and Laborator of Immunopharmacology (C.M.M.-M.) and Molecular Biology and Endemic Diseases (F.S.S., C.R.A.), Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil., Penido C; Laboratory of Applied Pharmacology, Institute of Drug Technology (P.V.B., K.H.M., P.P., M.d.G.H., C.P.), Computational Science Program, Computational Biophysics and Molecular Modeling Group (P.R.B.; E.R.C.), and Center for Technological Development in Health (M.G.H., C.P.), Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; and Laborator of Immunopharmacology (C.M.M.-M.) and Molecular Biology and Endemic Diseases (F.S.S., C.R.A.), Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil cpenido@cdts.fiocruz.br.
Jazyk:	angličtina
Zdroj:	Molecular pharmacology [Mol Pharmacol] 2015 Nov; Vol. 88 (5), pp. 949-61. Date of Electronic Publication: 2015 Sep 01.
DOI:	10.1124/mol.115.098970
Abstrakt:	Recognition of bacterial lipopolysaccharide (LPS) by innate immune system is mediated by the cluster of differentiation 14/Toll-like receptor 4/myeloid differentiation protein 2 (MD-2) complex. In this study, we investigated the modulatory effect of gedunin, a limonoid from species of the Meliaceae family described as a heat shock protein Hsp90 inhibitor, on LPS-induced response in immortalized murine macrophages. The pretreatment of wild-type (WT) macrophages with gedunin (0.01-100 µM, noncytotoxic concentrations) inhibited LPS (50 ng/ml)-induced calcium influx, tumor necrosis factor-α, and nitric oxide production in a concentration-dependent manner. The selective effect of gedunin on MyD88-adapter-like/myeloid differentiation primary response 88- and TRIF-related adaptor molecule/TIR domain-containing adapter-inducing interferon-β-dependent signaling pathways was further investigated. The pretreatment of WT, TIR domain-containing adapter-inducing interferon-β knockout, and MyD88 adapter-like knockout macrophages with gedunin (10 µM) significantly inhibited LPS (50 ng/ml)-induced tumor necrosis factor-α and interleukin-6 production, at 6 hours and 24 hours, suggesting that gedunin modulates a common event between both signaling pathways. Furthermore, gedunin (10 µM) inhibited LPS-induced prostaglandin E2 production, cyclooxygenase-2 expression, and nuclear factor κB translocation into the nucleus of WT macrophages, demonstrating a wide-range effect of this chemical compound. In addition to the ability to inhibit LPS-induced proinflammatory mediators, gedunin also triggered anti-inflammatory factors interleukin-10, heme oxygenase-1, and Hsp70 in macrophages stimulated or not with LPS. In silico modeling studies revealed that gedunin efficiently docked into the MD-2 LPS binding site, a phenomenon further confirmed by surface plasmon resonance. Our results reveal that, in addition to Hsp90 modulation, gedunin acts as a competitive inhibitor of LPS, blocking the formation of the Toll-like receptor 4/MD-2/LPS complex. (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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