Treatment with Anti-Interleukin-6 Receptor Antibody Ameliorates Intestinal Polyposis in Apc[Min/+] Mice under High-Fat Diet Conditions

Treatment with Anti-Interleukin-6 Receptor Antibody Ameliorates Intestinal Polyposis in Apc^Min/+ Mice under High-Fat Diet Conditions

TAKAO YAOITA,¹ YU SASAKI,¹ JUNJI YOKOZAWA,² TAKESHI SATO,^1,3 NANA KANNO,¹ KAZUHIRO SAKUTA,¹ MAKOTO YAGI,¹ KAZUYA YOSHIZAWA,¹ DAISUKE IWANO,¹ KO NAGINO,⁴ EIKI NOMURA,¹ YASUHIKO ABE,¹ SHOICHI NISHISE,¹ HIROAKI TAKEDA,⁵ SUMIO KAWATA⁶ and YOSHIYUKI UENO¹

¹Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Yamagata, Japan
²Department of Integrative Genomics, Tohoku Medical Megabank Organization, Sendai, Miyagi, Japan
³Division of Endoscopy, Yamagata University Hospital, Yamagata, Yamagata, Japan
⁴Yamagata City Hospital Saiseikan, Yamagata, Yamagata, Japan
⁵Department of Gastroenteorogy, Yamagata Prefectural Central Hospital, Yamagata, Yamagata, Japan
6 Hyogo Prefectural Nishinomiya Hospital, Nishinomiya, Hyogo, Japan

The prevalence of colorectal malignancies is increasing in the world. The parallel increase of metabolic syndrome gives a speculation between these two conditions, although the precise mechanism is still unclear. Interleukin-6 (IL-6) is a cytokine known to correlate with obesity and serve as a proinflammatory adipokine. In the present study, we investigated the effect of IL-6 signaling blockade on intestinal polyp formation in obesity using a mouse model of adenomatous polyposis coli (Apc). Male C57BL/6J-Apc^Min/+ mice were fed a high-fat diet from 5 weeks of age, and the overweight mice thus obtained were given a weekly intraperitoneal injection of anti-mouse IL-6 receptor antibody (MR16-1) from 6 to 15 weeks of age, while control mice received IgG or phosphate-buffered saline (PBS). The total number of intestinal polyps was significantly decreased in the MR16-1-injected group (53.1 ± 6.8) relative to the control groups (PBS-injected, 81.3 ± 6.1; rat IgG-injected, 74.7 ± 4.8, p = 0.01), and in particular the number of polyps larger than 2 mm in diameter was markedly decreased. In addition, the mean diameter of polyps in the MR16-1-injected group was significantly smaller than that in the control groups. On the other hand, no significant differences in body weight, epididymal fat pad mass, or the plasma levels of glucose, insulin and triglyceride were observed among the three groups. Thus, treatment with anti-IL-6 receptor antibody suppressed polyp growth in obese Apc^Min/+ mice fed the high-fat diet. We suggest that IL-6 signaling may be responsible for the obesity-associated colorectal tumorigenesis.

keywords —— Keywords: anti-interleukin-6 receptor antibody; colorectal cancer; inflammation; insulin resistance; metabolic syndrome

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Tohoku J. Exp. Med., 2015, 235, 127-134

Correspondence: Takeshi Sato, M.D., Department of Gastroenterology, Yamagata University Faculty of Medicine, 2-2-2 Iida-Nishi, Yamagata, Yamagata 990-9585, Japan.

e-mail: stakeshi@med.id.yamagata-u.ac.jp