title: Mice that express human interleukin-8 have increased mobilization of immature myeloid cells, which exacerbates inflammation and accelerates colon carcinogenesis.
abstract: OBJECTIVE
  Interleukin (IL)-8 has an important role in initiating inflammation in humans, attracting immune cells such as neutrophils through their receptors CXCR1 and CXCR2. IL-8 has been proposed to contribute to chronic inflammation and cancer. However, mice do not have the IL-8 gene, so human cancer cell lines and xenograft studies have been used to study the role of IL-8 in colon and gastric carcinogenesis. We generated mice that carry a bacterial artificial chromosome that encompasses the entire human IL-8 gene, including its regulatory elements (IL-8Tg mice).
  
  
  METHODS
  We studied the effects of IL-8 expression in APCmin(+/-) mice and IL-8Tg mice given azoxymethane and dextran sodium sulfate (DSS). We also examined the effects of IL-8 expression in gastric cancer in INS-GAS mice that overexpress gastrin and IL-8Tg mice infected with Helicobacter felis.
  
  
  RESULTS
  In IL-8Tg mice, expression of human IL-8 was controlled by its own regulatory elements, with virtually no messenger RNA or protein detectable under basal conditions. IL-8 was strongly up-regulated on systemic or local inflammatory stimulation, increasing mobilization of immature CD11b(+)Gr-1(+) myeloid cells (IMCs) with thioglycolate-induced peritonitis, DSS-induced colitis, and H. felis-induced gastritis. IL-8 was increased in colorectal tumors from patients and IL-8Tg mice compared with nontumor tissues. IL-8Tg mice developed more tumors than wild-type mice following administration of azoxymethane and DSS. Expression of IL-8 increased tumorigenesis in APCmin(+/-) mice compared with APCmin(+/-) mice that lack IL-8; this was associated with increased numbers of IMCs and angiogenesis in the tumors.
  
  
  CONCLUSIONS
  IL-8 contributes to gastrointestinal carcinogenesis by mobilizing IMCs and might be a therapeutic target for gastrointestinal cancers.
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Irving Cancer Research Center, Columbia University, New York, New York, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Asfaha
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Dubeykovskiy
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tomita
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Yang
authors.forename: Sarah
authors.initials: S
authors.lastname: Stokes
authors.forename: Wataru
authors.initials: W
authors.lastname: Shibata
authors.forename: Richard A
authors.initials: RA
authors.lastname: Friedman
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ariyama
authors.forename: Zinaida A
authors.initials: ZA
authors.lastname: Dubeykovskaya
authors.forename: Sureshkumar
authors.initials: S
authors.lastname: Muthupalani
authors.forename: Russell
authors.initials: R
authors.lastname: Ericksen
authors.forename: Harold
authors.initials: H
authors.lastname: Frucht
authors.forename: James G
authors.initials: JG
authors.lastname: Fox
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
mesh_terms: D000818:Animals; D001397:Azoxymethane; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D003713:Dendritic Cells / Q000378:metabolism; D016264:Dextran Sulfate; D005756:Gastritis / Q000378:metabolism* / Q000382:microbiology; D016481:Helicobacter Infections / Q000150:complications; D044922:Helicobacter felis; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000187:drug effects* / Q000378:metabolism; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000378:metabolism*; D047368:Tumor Burden; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016209:Interleukin-8; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D016264:Dextran Sulfate; D001397:Azoxymethane