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Originally published online as doi:10.1189/jlb.1206727 on July 3, 2007

Published online before print July 3, 2007
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(Journal of Leukocyte Biology. 2007;82:968-974.)
© 2007 by Society for Leukocyte Biology

MD-2 as the target of curcumin in the inhibition of response to LPS

Helena Gradisar, Mateja Mancek Keber, Primoz Pristovsek and Roman Jerala1

Laboratory of Biotechnology, National Institute of Chemistry, Ljubljana, Slovenia

1 Correspondence: Laboratory of Biotechnology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia. E-mail: roman.jerala{at}ki.si

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.

Key Words: Toll-like receptor 4 • fluorescence • molecular model • Asian enigma • gastric cancer




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