title: Thrombin-induced IL-8/CXCL8 release is mediated by CK2, MSK1, and NF-κB pathways in human lung epithelial cells.
abstract: Airway inflammation plays a major role in the pathophysiology of lung inflammatory diseases such as asthma. Thrombin, a serine protease, is known to mediate central functions in thrombosis and hemostasis and also plays a critical role in lung inflammation via producing chemokine release including interleukin (IL)-8/CXCL8. Our previous studies showed that c-Src- and Rac-dependent nuclear factor (NF)-κB signaling pathways participate in thrombin-induced IL-8/CXCL8 release in human lung epithelial cells. In this study, we further investigated the role of casein kinase 2 (CK2)/mitogen stress-activated protein kinase 1 (MSK1)-dependent p65 phosphorylation in thrombin-induced NF-κB activation and IL-8/CXCL8 release. Thrombin-induced IL-8/CXCL8 release was inhibited by CK2 inhibitors (apigenin and tetrabromobenzotriazole, TBB), small interfering RNA of CK2β (CK2β siRNA), and MSK1 siRNA. Treatment of cells with thrombin caused increases in CK2β phosphorylation at Ser209, which was inhibited by a protein kinase C α (PKCα) inhibitor (Ro-32-0432). Thrombin-induced MSK1 phosphorylation at Ser581 and Akt phosphorylation at Ser473 were inhibited by apigenin. Moreover, the thrombin-induced increase in IL-8/CXCL8 release was attenuated by p65 siRNA. Stimulation of cells with thrombin resulted in an increase in p65 phosphorylation at Ser276, which was inhibited by apigenin and MSK1 siRNA. Thrombin-induced κB-luciferase activity was also inhibited by apigenin and MSK1 siRNA. Taken together, these results show that thrombin activates the PKCα/CK2/MSK1 signaling pathways, which in turn initiates p65 phosphorylation and NF-κB activation, and ultimately induces IL-8/CXCL8 release in human lung epithelial cells.
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chien-Huang
authors.initials: CH
authors.lastname: Lin
authors.affiliation: School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan.
authors.forename: Chung-Hung
authors.initials: CH
authors.lastname: Shih
authors.affiliation: School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: bcchen@tmu.edu.tw.
authors.forename: Bing-Chang
authors.initials: BC
authors.lastname: Chen
mesh_terms: D000818:Animals; D047310:Apigenin / Q000494:pharmacology; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology
chemical_list: C405354:4,5,6,7-tetrabromobenzotriazole; C508606:CXCL8 protein, human; D007211:Indoles; D016209:Interleukin-8; D016328:NF-kappa B; D011758:Pyrroles; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D014230:Triazoles; C085989:Ro 32-0432; D047310:Apigenin; D047390:Casein Kinase II; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D013917:Thrombin
keywords: Casein kinase 2 (CK2); IL-8/CXCL8; Lung inflammation; Mitogen stress-activated protein kinase 1 (MSK1); Thrombin; p65