Advertisement

Inflammation Research

, Volume 58, Issue 5, pp 229–234 | Cite as

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
  • K. S. Prabhu
  • J. S. Bland
  • B. J. Carroll
  • M. L. Tripp
Article

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.

Keywords:

Inflammation COX-2 NF-κB Kinase inhibitor Bioavailability 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Copyright information

© Birkhäuser Verlag, Basel 2009

Authors and Affiliations

  • A. Desai
    • 1
  • V. R. Konda
    • 1
  • G. Darland
    • 1
  • M. Austin
    • 1
  • K. S. Prabhu
    • 2
  • J. S. Bland
    • 1
  • B. J. Carroll
    • 1
  • M. L. Tripp
    • 1
  1. 1.MetaProteomics Nutrigenomics Research Center, a subsidiary of Metagenics, Inc.Gig HarborUSA
  2. 2.Department of Veterinary and Biomedical Sciences and the Center for Molecular Toxicology and Carcinogenesis and Center for Molecular Immunology and Infectious DiseaseThe Pennsylvania State UniversityUniversity ParkUSA

Personalised recommendations