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Mice that express human interleukin-8 have increased mobilization of immature myeloid cells, which exacerbates inflammation and accelerates colon carcinogenesis
  • Samuel Asfaha, Columbia University
  • Alexander N. Dubeykovskiy, Columbia University
  • Hiroyuki Tomita, Columbia University
  • Xiangdong Yang, Columbia University
  • Sarah Stokes, Columbia University
  • Wataru Shibata, Columbia University
  • Richard A. Friedman, Columbia University
  • Hiroshi Ariyama, Columbia University
  • Zinaida A. Dubeykovskaya, Columbia University
  • Sureshkumar Muthupalani, Massachusetts Institute of Technology
  • Russell Ericksen, Columbia University
  • Harold Frucht, Columbia University
  • James G. Fox, Massachusetts Institute of Technology
  • Timothy C. Wang, Columbia University
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Background & Aims: 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. © 2013 AGA Institute.

Citation Information
Samuel Asfaha, Alexander N. Dubeykovskiy, Hiroyuki Tomita, Xiangdong Yang, et al.. "Mice that express human interleukin-8 have increased mobilization of immature myeloid cells, which exacerbates inflammation and accelerates colon carcinogenesis" Gastroenterology Vol. 144 Iss. 1 (2013) p. 155 - 166
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