title: Nicotine suppresses acute colitis and colonic tumorigenesis associated with chronic colitis in mice.
abstract: 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.
authors.affiliation: Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, Toyama, Japan; and hayashi@inm.u-toyama.ac.jp.
authors.forename: Shusaku
authors.initials: S
authors.lastname: Hayashi
authors.affiliation: Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, Toyama, Japan; and.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hamada
authors.affiliation: Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, Toyama, Japan; and.
authors.forename: Syed Faisal
authors.initials: SF
authors.lastname: Zaidi
authors.affiliation: Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, Toyama, Japan; and.
authors.forename: Momoe
authors.initials: M
authors.lastname: Oshiro
authors.affiliation: Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, Toyama, Japan; and.
authors.forename: Jaemin
authors.initials: J
authors.lastname: Lee
authors.affiliation: Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, Toyama, Japan; and.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ishii
authors.affiliation: Department of Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Masakiyo
authors.initials: M
authors.lastname: Sasahara
authors.affiliation: Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, Toyama, Japan; and.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kadowaki
mesh_terms: D000208:Acute Disease; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001397:Azoxymethane; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002908:Chronic Disease; D003092:Colitis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D003106:Colon / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D015536:Down-Regulation; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists* / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D016588:Anticarcinogenic Agents; C579166:Chrna7 protein, mouse; D005765:Gastrointestinal Agents; D018836:Inflammation Mediators; D015850:Interleukin-6; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D064569:alpha7 Nicotinic Acetylcholine Receptor; C577686:interleukin-6, mouse; D009538:Nicotine; D016264:Dextran Sulfate; D001397:Azoxymethane
keywords: CD4 T cells; dextran sulfate sodium-induced colitis; α7-nicotinic acetylcholine receptor