Abstract
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.
Highlights
Tumor necrosis factor alpha (TNF) is a potent proinflammatory cytokine and is an important therapeutic target for several chronic inflammatory diseases such as Rheumatoid Arthritis (RA)[1]
We hypothesized that inhibition of transforming growth factor Betaactivated kinase 1 (TAK1) with Takinib would significantly reduce pro-inflammatory cytokine secretion in stimulated macrophages
When compared to vehicle treated the following cytokines/chemokines were significantly reduced by Takinib treatment including GROα (P < 0.0004), IL-6 (P < 0.0001), IL-23 (P < 0.019), MCP-3 (P < 0.0006), TNF (P < 0.0001), and Thrombosbondin-1 (P < 0.0014) (Fig. 1b–g) and BAFF (P < 0.02), FGF-19 (P < 0.01), IGFBP-3 (P < 0.009), IL18Bpa (P < 0.008), MIP-3B (P < 0.001), Pentraxin 3 (P < 0.02) (Supplemental Fig. 1a)
Summary
Tumor necrosis factor alpha (TNF) is a potent proinflammatory cytokine and is an important therapeutic target for several chronic inflammatory diseases such as Rheumatoid Arthritis (RA)[1]. Relatively few small molecule drugs directly targeting TNF secretion have been discovered[7] Autoimmune disease such as RA are characterized by a hyperactivation of immune cells in the joints of patients resulting in elevated pro-inflammatory cytokines. Response to PAMPS is often mediated by pro-inflammatory molecular pathways leading to release of pro-inflammatory factors, which in turn further activate innate immune cells and the adaptive immune response[13] In diseases such as Rheumatoid Arthritis, the process normally used to fight pathogens can become dysregulated, engendering a hyper activated www.nature.com/scientificreports/. In this study we show Takinib potently reduces pro-inflammatory phenotypes and functional responses of the TLR4 receptor in response to LPS challenge This drug effect was recapitulated in THP-1 cells following TAK1 knock out using CRISPR/CAS9 targeted deletion. Takinib reduces TNF serum levels following LPS challenge in a murine model of sepsis
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