p300 and C/EBPβ-regulated IKKβ expression are involved in thrombin-induced IL-8/CXCL8 expression in human lung epithelial cells

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Abstract

Asthma and chronic obstructive pulmonary disease (COPD) are common chronic lung inflammatory diseases. Thrombin and interleukin (IL)-8/C-X-C chemokine ligand 8 (CXCL8) play critical roles in lung inflammation. Our previous study showed that c-Src-dependent IκB kinase (IKK)/IκBα/nuclear factor (NF)-κB and mitogen-activated protein kinase kinase kinase 1 (MEKK1)/extracellular signal-regulated kinase (ERK)/ribosomal S6 protein kinase (RSK)-dependent CAAT/enhancer-binding protein β (C/EBPβ) activation are involved in thrombin-induced IL-8/CXCL8 expression in human lung epithelial cells. In this study, we aimed to investigate the roles of p300 and C/EBPβ-reliant IKKβ expression in thrombin-induced IL-8/CXCL8 expression. Thrombin-induced increases in IL-8/CXCL8-luciferase activity and IL-8/CXCL8 release were inhibited by p300 small interfering (siRNA). Thrombin-caused histone H3 acetylation was attenuated by p300 siRNA. Stimulation of cells with thrombin for 12 h resulted in increases in IKKβ expression and phosphorylation in human lung epithelial cells. However, thrombin did not affect p65 expression. Moreover, 12 h of thrombin stimulation produced increases in IKKβ expression and phosphorylation, and IκBα phosphorylation, which were inhibited by C/EBPβ siRNA. Finally, treatment of cells with thrombin caused increases in p300 and C/EBPβ complex formation, p65 and C/EBPβ complex formation, and recruitment of p300, p65, and C/EBPβ to the IL-8/CXCL8 promoter. These results imply that p300-dependent histone H3 acetylation and C/EBPβ-regulated IKKβ expression contribute to thrombin-induced IL-8/CXCL8 expression in human lung epithelial cells. Results of this study will help clarify C/EBPβ signaling pathways involved in thrombin-induced IL-8/CXCL8 expression in human lung epithelial cells.

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