title: Cancer cell-derived IL-8 induces monocytic THP1 cells to secrete IL-8 via the mitogen-activated protein kinase pathway.
abstract: 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.
authors.affiliation: Division of Oral Structural and Functional Biology, Nihon University Graduate School of Dentistry, Tokyo, Japan.
authors.forename: Yukina
authors.initials: Y
authors.lastname: Nishio
authors.affiliation: Department of Pathology, Nihon University School of Dentistry, 1-8-13 Kanda Surugadai, Chiyoda-ku, Tokyo, 101-8310, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Gojoubori
authors.affiliation: Department of Pathology, Nihon University School of Dentistry, 1-8-13 Kanda Surugadai, Chiyoda-ku, Tokyo, 101-8310, Japan.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Kaneko
authors.affiliation: Department of Orthodontics, Nihon University School of Dentistry, Tokyo, Japan.
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Shimizu
authors.affiliation: Department of Pathology, Nihon University School of Dentistry, 1-8-13 Kanda Surugadai, Chiyoda-ku, Tokyo, 101-8310, Japan. asano.masatake@nihon-u.ac.jp.
authors.forename: Masatake
authors.initials: M
authors.lastname: Asano
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics*; D008264:Macrophages / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D009000:Monocytes / Q000473:pathology; D009062:Mouth Neoplasms / Q000235:genetics* / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; D020928:Mitogen-Activated Protein Kinases
keywords: Interleukin-8; Macrophage; Mitogen-activated protein kinase; Oral squamous cell carcinoma