Cancer cell-derived IL-8 induces monocytic THP1 cells to secrete IL-8 via the mitogen-activated protein kinase pathway
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Aberrant activity of transcription factors in oral squamous cell carcinoma (OSCC) results in the spontaneous secretion of various cytokines and chemokines. Among them, IL-8, owing to its angiogenic activity, promotes the growth of OSCCs. In the present study, we examined the role of IL-8 secreted by OSCCs, on the angiogenic activity of monocytic THP1 cells. Culture supernatant (Ca-sup) augmented IL-8 secretion by THP1 cells, which was found to be significantly reduced following the removal Ca9-22-derived IL-8 from the Ca-sup. IL-8 induction was regulated at the transcriptional level, because real-time PCR demonstrated the augmented IL-8 messenger RNA (mRNA) expression. We further performed the luciferase assay using the 5′-untranslated region of IL-8 gene. Contradictory to our speculations, luciferase activity was not augmented by Ca-sup stimulation. NF-κB-independent IL-8 induction was further confirmed by pre-treating THP1 cells with NF-κB-specific inhibitors. To elucidate the signaling pathway, THP1 was pre-treated with MEK inhibitors. The results demonstrated that pre-treatment of cells with MEK inhibitor drastically reduced IL-8 levels, suggesting the role of MEK. Moreover, Ca-sup was found to increase ERK1/2 phosphorylation in a time-dependent manner. These results indicated that OSCC-derived IL-8 appears to activate angiogenic activity in monocytes within the tumor microenvironment via the mitogen-activated protein kinase (MAPK) pathway.
KeywordsOral squamous cell carcinoma Interleukin-8 Macrophage Mitogen-activated protein kinase
This work was supported by a grant of Strategic Research Base Development Program for Private Universities from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (MEXT), 2010–2014 (S1001024); MEXT-supported program for the Strategic Research Foundation at Private Universities, 2013–2018; Sato Fund, Uemura Fund, and Grant from the Dental Research Center Nihon University School of Dentistry; and Nihon University Multidisciplinary Research Grant for 2015.
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