Hayashi Shusaku, Hamada Takayuki, Zaidi Syed Faisal, Oshiro Momoe, Lee Jaemin, Yamamoto Takeshi, Ishii Yoko, Sasahara Masakiyo, Kadowaki Makoto
Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, Toyama, Japan; and
Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, Toyama, Japan; and.
Am J Physiol Gastrointest Liver Physiol. 2014 Nov 15;307(10):G968-78. doi: 10.1152/ajpgi.00346.2013. Epub 2014 Sep 25.
Ulcerative colitis is a chronic inflammatory disease that frequently progresses to colon cancer. The tumor-promoting effect of inflammation is now widely recognized and understood. Recent studies have revealed that treatment with nicotine ameliorates colitis in humans and experimental murine models, whereas the effect of nicotine on colitis-associated colonic tumorigenesis remains unclear. In the present study, we examined the effect of nicotine on the development of acute colitis and colitis-associated cancer (CAC). The acute colitis model was induced by treatment with 3% dextran sulfate sodium (DSS) for 7 days, whereas the CAC model was induced by a combination of azoxymethane and repeated DSS treatment. Nicotine and a selective agonist of the α7-nicotinic acetylcholine receptor (α7-nAChR) reduced the severity of DSS-induced acute colonic inflammation. In addition, the suppressive effect of nicotine on acute colitis was attenuated by an antagonist of α7-nAChR. Furthermore, nicotine inhibited the IL-6 production of CD4 T cells in the DSS-induced inflamed colonic mucosa. We found that nicotine significantly reduced the number and size of colonic tumors in mice with CAC. Nicotine markedly inhibited the elevation of TNF-α and IL-6 mRNA as well as phosphorylated signal transducer and activator of transcription (Stat) 3 expression in the colons of the tumor model mice. These results demonstrate that nicotine suppresses acute colitis and colitis-associated tumorigenesis, and this effect may be associated with the activation of α7-nAChR. Furthermore, it is presumed that nicotine downregulates the expression of inflammatory mediators such as IL-6/Stat3 and TNF-α, thereby reducing the colonic tumorigenesis associated with chronic colitis.
溃疡性结肠炎是一种慢性炎症性疾病，常进展为结肠癌。炎症的促肿瘤作用现已得到广泛认可和理解。最近的研究表明，尼古丁治疗可改善人类和实验性小鼠模型中的结肠炎，而尼古丁对结肠炎相关结肠肿瘤发生的影响仍不清楚。在本研究中，我们研究了尼古丁对急性结肠炎和结肠炎相关癌症（CAC）发生发展的影响。急性结肠炎模型通过用3%硫酸葡聚糖钠（DSS）处理7天诱导，而CAC模型通过偶氮甲烷和重复DSS处理联合诱导。尼古丁和α7-烟碱型乙酰胆碱受体（α7-nAChR）的选择性激动剂降低了DSS诱导的急性结肠炎症的严重程度。此外，α7-nAChR拮抗剂减弱了尼古丁对急性结肠炎的抑制作用。此外，尼古丁抑制了DSS诱导的炎症性结肠黏膜中CD4 T细胞的IL-6产生。我们发现尼古丁显著减少了CAC小鼠结肠肿瘤的数量和大小。尼古丁显著抑制了肿瘤模型小鼠结肠中TNF-α和IL-6 mRNA的升高以及磷酸化信号转导和转录激活因子（Stat）3的表达。这些结果表明，尼古丁抑制急性结肠炎和结肠炎相关的肿瘤发生，这种作用可能与α7-nAChR的激活有关。此外，推测尼古丁下调IL-6/Stat3和TNF-α等炎症介质的表达，从而减少与慢性结肠炎相关的结肠肿瘤发生。
