S Yang1, W Zhao1, X Peng1, Z Lan1, J Huang1, H Han1, Y Chen1, S Cai1, H Zhao1. 1. Laboratory of Chronic Airway Diseases, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Abstract
OBJECTIVE: To explore the effect of transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) on toluene diisocyanate (TDI)-induced allergic airway inflammation in mice. METHODS: Thirty-two mice were randomly divided into AOO group, AOO+5Z-7-Oxozeaenol group, TDI group, and TDI+5Z-7-Oxozeaenol group. Another 32 mice were randomly divided into AOO group, TDI group, TDI +5Z-7-Oxozeaenol group, and TDI +5Z-7-Oxozeaenol + Necrostatin-1 group. TAK1 inhibitor (5Z-7-Oxozeaenol, 5 mg/kg) and/or RIPK1 inhibitor (Necrostatin-1, 5 mg/kg) were used before each challenge. Airway responsiveness, airway inflammation and airway remodeling were assessed after the treatments. We also examined the effect of TDI-human serum albumin (TDI-HSA) conjugate combined with TAK1 inhibitor on the viability of mouse mononuclear macrophages (RAW264.7) using CCK8 assay. The expressions of TAK1, mitogen-activated protein kinase (MAPK) and receptor interacting serine/threonine protease 1 (RIPK1) signal pathway in the treated cells were detected with Western blotting. The effects of RIPK1 inhibitor on the viability of RAW264.7 cells and airway inflammation of the mouse models of TDI-induced asthma were evaluated. RESULTS: TAK1 inhibitor aggravated TDI-induced airway inflammation, airway hyper responsiveness and airway remodeling in the mouse models (P < 0.05). Treatment with TAK1 inhibitor significantly decreased the viability of RAW264.7 cells, which was further decreased by co-treatment with TDI-HSA (P < 0.05). TAK1 inhibitor significantly decreased the level of TAK1 phosphorylation and activation of MAPK signal pathway induced by TDI-HSA (P < 0.05). Co-treatment with TAK1 inhibitor and TDI-HSA obviously increased the level of RIPK1 phosphorylation and caused persistent activation of caspase 8 (P < 0.05). RIPK1 inhibitor significantly inhibited the reduction of cell viability caused by TAK1 inhibitor and TDI-HSA (P < 0.05) and alleviated the aggravation of airway inflammation induced by TAK1 inhibitors in TDI-induced mouse models (P < 0.05). CONCLUSION: Inhibition of TAK1 aggravates TDI-induced airway inflammation and hyperresponsiveness and may increase the death of macrophages by enhancing the activity of RIPK1 and causing persistent activation of caspase 8.
OBJECTIVE: To explore the effect of transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) on toluene diisocyanate (TDI)-induced allergic airway inflammation in mice. METHODS: Thirty-two mice were randomly divided into AOO group, AOO+5Z-7-Oxozeaenol group, TDI group, and TDI+5Z-7-Oxozeaenol group. Another 32 mice were randomly divided into AOO group, TDI group, TDI +5Z-7-Oxozeaenol group, and TDI +5Z-7-Oxozeaenol + Necrostatin-1 group. TAK1 inhibitor (5Z-7-Oxozeaenol, 5 mg/kg) and/or RIPK1 inhibitor (Necrostatin-1, 5 mg/kg) were used before each challenge. Airway responsiveness, airway inflammation and airway remodeling were assessed after the treatments. We also examined the effect of TDI-human serum albumin (TDI-HSA) conjugate combined with TAK1 inhibitor on the viability of mouse mononuclear macrophages (RAW264.7) using CCK8 assay. The expressions of TAK1, mitogen-activated protein kinase (MAPK) and receptor interacting serine/threonine protease 1 (RIPK1) signal pathway in the treated cells were detected with Western blotting. The effects of RIPK1 inhibitor on the viability of RAW264.7 cells and airway inflammation of the mouse models of TDI-induced asthma were evaluated. RESULTS: TAK1 inhibitor aggravated TDI-induced airway inflammation, airway hyper responsiveness and airway remodeling in the mouse models (P < 0.05). Treatment with TAK1 inhibitor significantly decreased the viability of RAW264.7 cells, which was further decreased by co-treatment with TDI-HSA (P < 0.05). TAK1 inhibitor significantly decreased the level of TAK1 phosphorylation and activation of MAPK signal pathway induced by TDI-HSA (P < 0.05). Co-treatment with TAK1 inhibitor and TDI-HSA obviously increased the level of RIPK1 phosphorylation and caused persistent activation of caspase 8 (P < 0.05). RIPK1 inhibitor significantly inhibited the reduction of cell viability caused by TAK1 inhibitor and TDI-HSA (P < 0.05) and alleviated the aggravation of airway inflammation induced by TAK1 inhibitors in TDI-induced mouse models (P < 0.05). CONCLUSION: Inhibition of TAK1 aggravates TDI-induced airway inflammation and hyperresponsiveness and may increase the death of macrophages by enhancing the activity of RIPK1 and causing persistent activation of caspase 8.
Authors: Elena Goleva; Leisa P Jackson; J Kirk Harris; Charles E Robertson; E Rand Sutherland; Clifton F Hall; James T Good; Erwin W Gelfand; Richard J Martin; Donald Y M Leung Journal: Am J Respir Crit Care Med Date: 2013-11-15 Impact factor: 21.405
Authors: Douglas S Jones; Anne P Jenney; Jennifer L Swantek; John M Burke; Douglas A Lauffenburger; Peter K Sorger Journal: Nat Chem Biol Date: 2016-10-31 Impact factor: 16.174