Genetic and pharmacological validation of TAK1 inhibition in macrophages as a therapeutic strategy to effectively inhibit TNF secretion
Autor: | Liesl S. Eibschutz, David E. Carlson, David R. Loiselle, Scott A. Scarneo, Philip F. Hughes, Timothy A.J. Haystead, Antoine Mansourati, Juliane Totzke, Jose R. Roques |
---|---|
Rok vydání: | 2018 |
Předmět: |
Male
0301 basic medicine Lipopolysaccharide p38 mitogen-activated protein kinases lcsh:Medicine Article Proinflammatory cytokine Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Immune system medicine Animals Interferon gamma lcsh:Science 030203 arthritis & rheumatology Multidisciplinary biology Tumor Necrosis Factor-alpha Macrophages lcsh:R Transforming growth factor beta MAP Kinase Kinase Kinases medicine.disease 3. Good health Mice Inbred C57BL 030104 developmental biology chemistry Immunology biology.protein lcsh:Q Female Tumor necrosis factor alpha Cytokine storm medicine.drug |
Zdroj: | Scientific Reports Scientific Reports, Vol 8, Iss 1, Pp 1-11 (2018) |
ISSN: | 2045-2322 |
Popis: | 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. |
Databáze: | OpenAIRE |
Externí odkaz: |