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IL (Interleukin)-1 Promotes Nuclear Factor-B and AP-1-induced IL-8 Expression, Cell Survival, and Proliferation in Head and Neck Squamous Cell Carcinomas¹

Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland, 20892 [J. S. W, Z. C., G. D., J. B. S., C. C. B., D. E. C., N. T. Y., C. V. W.]; and Division of Molecular Pharmacology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan [N. M.]

Interleukin 1 (IL-1) is an important regulatory cytokine, the release of which after an injury can induce activation of transcription factors nuclear factor (NF)B and activator protein (AP-1), which promote expression of genes involved in cell survival, proliferation, and angiogenesis. IL-1 is expressed autonomously by head and neck squamous cell carcinomas (HNSCCs) and a variety of other cancers, raising the possibility that IL-1 may serve as an autocrine factor that stimulates the activation of prosurvival transcription factors and target genes in cancer. In this study, we examined the role of IL-1 in the activation of NFB and AP-1, the expression of proangiogenic cytokine IL-8, and in the survival and proliferation of HNSCC cell lines. HNSCCs were found to secrete and respond to functional IL-1, in that culture supernatant from a high IL-1-secreting line, UM-SCC-11B, could induce secretion of cytokine IL-8 by a low IL-1-secreting line, UM-SCC-9; and the induction of IL-8 secretion could be blocked by the anti-IL-1-neutralizing antibody or the IL-1 receptor antagonist (IL-1RA). Furthermore, IL-1 could induce the expression of IL-8 through an autocrine mechanism, in that transfection of UM-SCC-9 cells with a plasmid encoding IL-1 resulted in the increased coexpression of IL-1 and IL-8; whereas transfection with a plasmid encoding IL-1RA lacking the secretory leader sequence led to the decreased coexpression of IL-1 and IL-8. IL-1 was found to induce coexpression of IL-8 through the activation of NFB and AP-1, in that mutation of the NFB site within the IL-8 promoter abolished autocrine- and recombinant IL-1-induced IL-8 reporter gene activity, whereas mutation in AP-1 partially decreased IL-8 reporter gene activity in UM-SCC-9 cells. Intracellular expression of IL-1RA decreased NFB reporter gene activity, indicating that endogenously expressed IL-1 contributes to constitutive NFB activation in this HNSCC line. Expression of IL-1 affected survival of UM-SCC-9, inasmuch as transfection of cells with plasmid encoding IL-1 or IL-1RA led to the increased or decreased survival of cells cotransfected with a ß-galactosidase reporter gene, respectively. IL-1 was also found to promote the increased growth of UM-SCC-9 cells in vitro. We demonstrate that exogenous and endogenous IL-1 contributes to the transcriptional activation of NFB and AP-1, to the expression of IL-8, and to cell survival and the growth of HNSCC in vitro.

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