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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Published in | Inflammation research Vol. 58; no. 5; p. 229 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
New York
Springer Nature B.V
01.05.2009
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Online Access | Get full text |
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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. |
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ISSN: | 1023-3830 1420-908X |
DOI: | 10.1007/s00011-008-8162-y |