Mice that express human interleukin-8 have increased mobilization of immature myeloid cells, which exacerbates inflammation and accelerates colon carcinogenesis

Gastroenterology. 2013 Jan;144(1):155-66. doi: 10.1053/j.gastro.2012.09.057. Epub 2012 Oct 3.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azoxymethane
  • Cell Line, Tumor
  • Cell Movement / drug effects*
  • Cell Transformation, Neoplastic / metabolism*
  • Colitis / chemically induced
  • Colitis / metabolism*
  • Colonic Neoplasms / chemically induced
  • Colonic Neoplasms / metabolism*
  • Colonic Neoplasms / pathology
  • Dendritic Cells / metabolism
  • Dextran Sulfate
  • Gastritis / metabolism*
  • Gastritis / microbiology
  • Helicobacter Infections / complications
  • Helicobacter felis
  • Humans
  • Interleukin-8 / genetics
  • Interleukin-8 / metabolism*
  • Interleukin-8 / pharmacology
  • Lipopolysaccharides / pharmacology
  • Macrophages / metabolism
  • Mice
  • Mice, Transgenic
  • Myeloid Cells / drug effects*
  • Myeloid Cells / metabolism
  • Primary Cell Culture
  • RNA, Messenger / metabolism*
  • Tumor Burden
  • Up-Regulation / drug effects


  • Interleukin-8
  • Lipopolysaccharides
  • RNA, Messenger
  • Dextran Sulfate
  • Azoxymethane