title: MD-2 as the target of curcumin in the inhibition of response to LPS.
abstract: Curcumin is the main constituent of the spice turmeric, used in diet and in traditional medicine, particularly across the Indian subcontinent. Anti-inflammatory activity and inhibition of LPS signaling are some of its many activities. We show that curcumin binds at submicromolar affinity to the myeloid differentiation protein 2 (MD-2), which is the LPS-binding component of the endotoxin surface receptor complex MD-2/TLR4. Fluorescence emission of curcumin increases with an absorbance maximum shift toward the blue upon the addition of MD-2, indicating the transfer of curcumin into the hydrophobic environment. Curcumin does not form a covalent bond to the free thiol group of MD-2, and C133F mutant retains the binding and inhibition by curcumin. The binding site for curcumin overlaps with the binding site for LPS. This results in the inhibition of MyD88-dependent and -independent signaling pathways of LPS signaling through TLR4, indicating that MD-2 is one of the important targets of curcumin in its suppression of the innate immune response to bacterial infection. This finding, in addition to the correlation between the dietary use of curcumin and low incidence of gastric cancer in India, may have important implications for treatment and epidemiology of chronic inflammatory diseases caused by bacterial infection.
authors.affiliation: National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia.
authors.forename: Helena
authors.initials: H
authors.lastname: Gradisar
authors.forename: Mateja Mancek
authors.initials: MM
authors.lastname: Keber
authors.forename: Primoz
authors.initials: P
authors.lastname: Pristovsek
authors.forename: Roman
authors.initials: R
authors.lastname: Jerala
mesh_terms: D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001424:Bacterial Infections / Q000276:immunology; D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D002908:Chronic Disease; D003474:Curcumin / Q000494:pharmacology*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D007194:India; D007249:Inflammation / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051218:Lymphocyte Antigen 96 / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D020125:Mutation, Missense; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology*; D013274:Stomach Neoplasms / Q000453:epidemiology / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology*
chemical_list: D000970:Antineoplastic Agents; C495377:LY96 protein, human; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D003474:Curcumin