META060 inhibits multiple kinases in the NF-κB pathway and suppresses LPS - Mediated inflammation in vitro and ex vivo

A. Desai, V. R. Konda, G. Darland, M. Austin, Kumble Sandeep Prabhu, J. S. Bland, B. J. Carroll, M. L. Tripp

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Objective: 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. Methods: 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. Results: 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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)229-234
Number of pages6
JournalInflammation Research
Volume58
Issue number5
DOIs
StatePublished - May 1 2009

All Science Journal Classification (ASJC) codes

  • Immunology
  • Pharmacology

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