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

• Published in: Inflammation research Vol. 58; no. 5; pp. 229 - 234
• 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
• Language: English
• Published: Basel Birkhäuser-Verlag 01.05.2009
• Subjects: Allergology; Biomedical and Life Sciences; Biomedicine; Dermatology; Immunology; Neurology; Pharmacology/Toxicology; Rheumatology; NF-κB; Inflammation; Bioavailability; COX-2; Kinase inhibitor
• ISSN: 1023-3830; 1420-908X
• DOI: 10.1007/s00011-008-8162-y

. 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 E 2 , 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 E 2 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.