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

Authors

Samuel Asfaha, Columbia UniversityFollow
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

Document Type

Article

Publication Date

1-1-2013

Journal

Gastroenterology

Volume

144

Issue

1

First Page

155

Last Page

166

URL with Digital Object Identifier

10.1053/j.gastro.2012.09.057

Abstract

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.