IL (interleukin)-1alpha promotes nuclear factor-kappaB and AP-1-induced IL-8 expression, cell survival, and proliferation in head and neck squamous cell carcinomas.
IL (interleukin)-1alpha promotes nuclear factor-kappaB and AP-1-induced IL-8 expression, cell survival, and proliferation in head and neck squamous cell carcinomas.
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发表时间：
2001
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通讯作者：
J. Wolf;Z. Chen;G. Dong;J. Sunwoo;C. Bancroft;D. Capo;N. Yeh;N. Mukaida;C. Van Waes
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作者：
J. Wolf;Z. Chen;G. Dong;J. Sunwoo;C. Bancroft;D. Capo;N. Yeh;N. Mukaida;C. Van Waes
白细胞介素1 α（IL-1 α）是一种重要的调节性细胞因子，其在损伤后的释放可诱导转录因子核因子（NF）κ B和激活蛋白（AP-1）的激活，其促进参与细胞存活、增殖和血管生成的基因的表达。IL-1 α由头颈部鳞状细胞癌（HNSCC）和多种其他癌症自主表达，这增加了IL-1 α可能作为自分泌因子刺激癌症中促生存转录因子和靶基因活化的可能性。在这项研究中，我们研究了IL-1 α在NF κ B和AP-1的激活、促血管生成细胞因子IL-8的表达以及HNSCC细胞系的存活和增殖中的作用。HNSCC分泌IL-1 α并对IL-1 α产生应答，高IL-1 α分泌细胞系UM-SCC-11B培养上清可诱导低IL-1 α分泌细胞系UM-SCC-9分泌细胞因子IL-8，IL-8的诱导分泌可被抗IL-1 α中和抗体或IL-1受体拮抗剂（IL-1 RA）阻断。此外，IL-1 α可以通过自分泌机制诱导IL-8的表达，用编码IL-1 α的质粒转染UM-SCC-9细胞导致IL-1 α和IL-8的共表达增加;而用编码缺乏分泌前导序列的IL-1 RA的质粒转染导致IL-1 α和IL-8的共表达减少。发现IL-1 α通过激活NF κ B和AP-1诱导IL-8的共表达，即IL-8启动子内NF κ B位点的突变消除了自分泌和重组IL-1 α诱导的IL-8报告基因活性，而AP-1突变部分降低了UM-SCC-9细胞中IL-8报告基因活性。IL-1 RA的细胞内表达降低了NF κ B报告基因的活性，表明内源性表达的IL-1 α有助于该HNSCC系中的组成性NF κ B活化。IL-1 α的表达影响UM-SCC-9的存活，因为用编码IL-1 α或IL-1 RA的质粒转染细胞分别导致与β-半乳糖苷酶报告基因共转染的细胞的存活增加或减少。IL-1 α还被发现在体外促进UM-SCC-9细胞的生长增加。我们证明，外源性和内源性IL-1 α有助于NF κ B和AP-1的转录激活，IL-8的表达，以及细胞存活和体外HNSCC的生长。
Interleukin 1alpha (IL-1alpha) is an important regulatory cytokine, the release of which after an injury can induce activation of transcription factors nuclear factor (NF)kappaB and activator protein (AP-1), which promote expression of genes involved in cell survival, proliferation, and angiogenesis. IL-1alpha is expressed autonomously by head and neck squamous cell carcinomas (HNSCCs) and a variety of other cancers, raising the possibility that IL-1alpha 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-1alpha in the activation of NFkappaB 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-1alpha, in that culture supernatant from a high IL-1alpha-secreting line, UM-SCC-11B, could induce secretion of cytokine IL-8 by a low IL-1alpha-secreting line, UM-SCC-9; and the induction of IL-8 secretion could be blocked by the anti-IL-1alpha-neutralizing antibody or the IL-1 receptor antagonist (IL-1RA). Furthermore, IL-1alpha could induce the expression of IL-8 through an autocrine mechanism, in that transfection of UM-SCC-9 cells with a plasmid encoding IL-1alpha resulted in the increased coexpression of IL-1alpha and IL-8; whereas transfection with a plasmid encoding IL-1RA lacking the secretory leader sequence led to the decreased coexpression of IL-1alpha and IL-8. IL-1alpha was found to induce coexpression of IL-8 through the activation of NFkappaB and AP-1, in that mutation of the NFkappaB site within the IL-8 promoter abolished autocrine- and recombinant IL-1alpha-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 NFkappaB reporter gene activity, indicating that endogenously expressed IL-1alpha contributes to constitutive NFkappaB activation in this HNSCC line. Expression of IL-1alpha affected survival of UM-SCC-9, inasmuch as transfection of cells with plasmid encoding IL-1alpha or IL-1RA led to the increased or decreased survival of cells cotransfected with a beta-galactosidase reporter gene, respectively. IL-1alpha was also found to promote the increased growth of UM-SCC-9 cells in vitro. We demonstrate that exogenous and endogenous IL-1alpha contributes to the transcriptional activation of NFkappaB and AP-1, to the expression of IL-8, and to cell survival and the growth of HNSCC in vitro.