Inflammation Research

, Volume 58, Issue 5, pp 229–234

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

Authors

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

DOI: 10.1007/s00011-008-8162-y

Cite this article as:
Desai, A., Konda, V.R., Darland, G. et al. Inflamm. Res. (2009) 58: 229. doi:10.1007/s00011-008-8162-y

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:

InflammationCOX-2NF-κBKinase inhibitorBioavailability

Copyright information

© Birkhäuser Verlag, Basel 2009