META060 inhibits multiple kinases in the NF-[kappa]B pathway and suppresses LPS - mediated inflammation in vitro and ex vivo

We investigated whether a novel candidate META060 targeted the inflammatory signal transduction without affecting constitutive COX-2 enzymatic activity in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. We also investigated its bioavailability in humans and its anti-inflammatory effect ex...

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Bibliographic Details
Published inInflammation research Vol. 58; no. 5; p. 229
Main Authors Desai, A, Konda, V R, Darland, G, Austin, M, Prabhu, K S, Bland, J S, Carroll, B J, Tripp, M L
Format Journal Article
LanguageEnglish
Published New York Springer Nature B.V 01.05.2009
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Summary:We investigated whether a novel candidate META060 targeted the inflammatory signal transduction without affecting constitutive COX-2 enzymatic activity in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. We also investigated its bioavailability in humans and its anti-inflammatory effect ex vivo. We measured prostaglandin E2, nitric oxide, TNFα and IL-6 by ELISA, COX-2 protein by Western blot, NF-κB nuclear binding by electrophoretic mobility shift assays, and NF-κB activation by luciferase assay. Kinase inhibitions were measured by cell-free assays. Bioavailability was tested in 4 human subjects consuming 940 mg META060. LPS-activated TNFα and IL-6 were measured in peripheral blood mononuclear cells (PBMC) isolated from 1 subject up to 6 hours post administration. META060 dose-dependently inhibited prostaglandin E2 and nitric oxide formation, COX-2 abundance, and NF-κB activation. In cell-free assays, META060 inhibited multiple kinases in the NF-κB signaling pathway, including BTK, PI3K, and GSK3. META060 was detected in the plasma of the subjects; isolated PBMC were resistant to LPS-stimulated TNFα and IL-6 production. Without inhibiting COX-2 enzyme, META060 reduces the inflammation by inhibiting multiple kinases involved in NF-κB pathway, and may have potential as a safe anti-inflammatory therapeutic.
ISSN:1023-3830
1420-908X
DOI:10.1007/s00011-008-8162-y