Genetic and pharmacological validation of TAK1 inhibition in macrophages as a therapeutic strategy to effectively inhibit TNF secretion.
Scott A ScarneoAntoine MansouratiLiesl S EibschutzJuliane TotzkeJose R RoquesDavid LoiselleDavid A CarlsonPhilip F HughesTimothy A J HaysteadPublished in: Scientific reports (2018)
Immune challenge of invading macrophages at sites of infection is associated with release of TNF, which triggers a local cytokine storm as part of the normal inflammatory response. Whereas this response maybe beneficial in fighting off infections, similar responses triggered in autoimmune diseases contribute significantly to the underlying damaging pathology associated with these diseases. Here we show that Takinib, a highly discriminatory inhibitor of transforming growth factor Beta- activated kinase 1 (TAK1), selectively and potently reduces TNF production in pro-inflammatory THP-1 macrophages. A complete survey of 110 cytokines, showed robust loss of proinflammatory cytokine responsiveness to lipopolysaccharide (LPS) and interferon gamma (IFNγ) challenge in response to Takinib. The mechanisms of action of Takinib was recapitulated in TAK1 KO macrophages. TAK1 KO cells showed significant loss of TNF production as well as release of IL-6 in response to LPS challenge. Furthermore, Takinib blocked the ability of exogenously added LPS to promote phosphorylation of, c-Jun, p38 protein kinases as well as downstream transcription factors regulated by nuclear factor κ-light-chain-enhancer of activated B cells (NFκB). In a mouse LPS challenge model, Takinib significantly reduced TNF serum levels. Our findings demonstrate that Takinib has utility in the treatment inflammatory disease by locally suppressing TNF production from invading macrophages.
Keyphrases
- inflammatory response
- rheumatoid arthritis
- nuclear factor
- toll like receptor
- lps induced
- transforming growth factor
- lipopolysaccharide induced
- transcription factor
- anti inflammatory
- signaling pathway
- oxidative stress
- epithelial mesenchymal transition
- induced apoptosis
- dendritic cells
- gene expression
- immune response
- genome wide