ArticleRespiratory research2025
Serine/threonine kinase 33 mediates thrombin-induced interleukin-8 release from human lung epithelial cells in severe asthma.
Article in Respiratory research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Interleukin (IL)-8, also known as chemokine (CXC motif) ligand 8, contributes to the pathogenesis of neutrophilic asthma. Thrombin exacerbates IL-8/CXCL8-mediated inflammatory responses. However, the underlying mechanisms remain unclear. Phosphorylation of serine/threonine kinase 33 (STK33) by extracellular signal-regulated kinase (ERK) has been implicated in lung cancer metastasis, but its role in thrombin-induced airway inflammation remains to be determined. In this study, we investigated whether STK33 mediates thrombin-induced IL-8/CXCL8 release from airway epithelial cells in severe asthma. Single-cell RNA sequencing revealed upregulated STK33 expression in bronchial epithelial cells from patients with severe asthma. Immunofluorescence staining indicated increased coexpression of STK33 and macrophage inflammatory protein 2 (murine homolog of IL-8/CXCL8) in the airway epithelial cells of mice with ovalbumin- and house dust mite–induced asthma. Thrombin induced STK33 phosphorylation at serine residues. Notably, STK33 knockdown markedly inhibited thrombin-induced IL-8/CXCL8 release from A549 and BEAS-2B cells. Thrombin also induced the formation of an ERK–STK33 complex, and STK33 knockdown reduced thrombin-induced ERK phosphorylation. Colocalization of STK33, p-c-Myc, and thrombin was increased in asthmatic mice. Moreover, thrombin increased the phosphorylation of c-Myc in A549 cells; this increase in c-Myc phosphorylation was significantly attenuated by ERK inhibition (U0126 treatment) and STK33 knockdown. Furthermore, thrombin promoted the binding of c-Myc to the IL-8/CXCL8 promoter, and c-Myc knockdown suppressed thrombin-induced IL-8/CXCL8 release from A549 and BEAS-2B cells. Collectively, these findings indicate that thrombin induces IL-8/CXCL8 release through the ERK/STK33/c-Myc pathway, highlighting STK33 as a potential therapeutic target in severe asthma.
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