Mice That Express Human Interleukin-8 Have Increased Mobilization of Immature Myeloid Cells, Which Exacerbates Inflammation and Accelerates Colon Carcinogenesis
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,...
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| Muut tekijät: | |
| Aineistotyyppi: | Artikkeli |
| Kieli: | en_US |
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Elsevier
2015
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| Linkit: | http://hdl.handle.net/1721.1/99370 https://orcid.org/0000-0001-9307-6116 |
| _version_ | 1826199501246824448 |
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| author | Asfaha, Samuel Dubeykovskiy, Alexander N. Tomita, Hiroyuki Yang, Xiangdong Stokes, Sarah Shibata, Wataru Friedman, Richard A. Ariyama, Hiroshi Dubeykovskaya, Zinaida A. Muthupalani, Sureshkumar Ericksen, Russell Frucht, Harold Fox, James G. Wang, Timothy C. |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Asfaha, Samuel Dubeykovskiy, Alexander N. Tomita, Hiroyuki Yang, Xiangdong Stokes, Sarah Shibata, Wataru Friedman, Richard A. Ariyama, Hiroshi Dubeykovskaya, Zinaida A. Muthupalani, Sureshkumar Ericksen, Russell Frucht, Harold Fox, James G. Wang, Timothy C. |
| author_sort | Asfaha, Samuel |
| collection | MIT |
| description | 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[superscript +/−] 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[superscript +]Gr-1[superscript +] 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[superscript +/−] mice compared with APCmin[superscript +/−] 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. |
| first_indexed | 2024-09-23T11:21:16Z |
| format | Article |
| id | mit-1721.1/99370 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:21:16Z |
| publishDate | 2015 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/993702022-09-27T18:55:30Z Mice That Express Human Interleukin-8 Have Increased Mobilization of Immature Myeloid Cells, Which Exacerbates Inflammation and Accelerates Colon Carcinogenesis Asfaha, Samuel Dubeykovskiy, Alexander N. Tomita, Hiroyuki Yang, Xiangdong Stokes, Sarah Shibata, Wataru Friedman, Richard A. Ariyama, Hiroshi Dubeykovskaya, Zinaida A. Muthupalani, Sureshkumar Ericksen, Russell Frucht, Harold Fox, James G. Wang, Timothy C. Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Division of Comparative Medicine Muthupalani, Sureshkumar Fox, James G. 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[superscript +/−] 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[superscript +]Gr-1[superscript +] 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[superscript +/−] mice compared with APCmin[superscript +/−] 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. 2015-10-20T13:04:39Z 2015-10-20T13:04:39Z 2012-10 2011-10 Article http://purl.org/eprint/type/JournalArticle 00165085 1528-0012 http://hdl.handle.net/1721.1/99370 Asfaha, Samuel, Alexander N. Dubeykovskiy, Hiroyuki Tomita, Xiangdong Yang, Sarah Stokes, Wataru Shibata, Richard A. Friedman, et al. “Mice That Express Human Interleukin-8 Have Increased Mobilization of Immature Myeloid Cells, Which Exacerbates Inflammation and Accelerates Colon Carcinogenesis.” Gastroenterology 144, no. 1 (January 2013): 155–66. https://orcid.org/0000-0001-9307-6116 en_US http://dx.doi.org/10.1053/j.gastro.2012.09.057 Gastroenterology Creative Commons Attribution http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier Elsevier |
| spellingShingle | Asfaha, Samuel Dubeykovskiy, Alexander N. Tomita, Hiroyuki Yang, Xiangdong Stokes, Sarah Shibata, Wataru Friedman, Richard A. Ariyama, Hiroshi Dubeykovskaya, Zinaida A. Muthupalani, Sureshkumar Ericksen, Russell Frucht, Harold Fox, James G. Wang, Timothy C. Mice That Express Human Interleukin-8 Have Increased Mobilization of Immature Myeloid Cells, Which Exacerbates Inflammation and Accelerates Colon Carcinogenesis |
| title | Mice That Express Human Interleukin-8 Have Increased Mobilization of Immature Myeloid Cells, Which Exacerbates Inflammation and Accelerates Colon Carcinogenesis |
| title_full | Mice That Express Human Interleukin-8 Have Increased Mobilization of Immature Myeloid Cells, Which Exacerbates Inflammation and Accelerates Colon Carcinogenesis |
| title_fullStr | Mice That Express Human Interleukin-8 Have Increased Mobilization of Immature Myeloid Cells, Which Exacerbates Inflammation and Accelerates Colon Carcinogenesis |
| title_full_unstemmed | Mice That Express Human Interleukin-8 Have Increased Mobilization of Immature Myeloid Cells, Which Exacerbates Inflammation and Accelerates Colon Carcinogenesis |
| title_short | Mice That Express Human Interleukin-8 Have Increased Mobilization of Immature Myeloid Cells, Which Exacerbates Inflammation and Accelerates Colon Carcinogenesis |
| title_sort | mice that express human interleukin 8 have increased mobilization of immature myeloid cells which exacerbates inflammation and accelerates colon carcinogenesis |
| url | http://hdl.handle.net/1721.1/99370 https://orcid.org/0000-0001-9307-6116 |
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