Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Research Article
  • Published:

Expression of the novel adipokine C1qTNF-related protein 4 (CTRP4) suppresses colitis and colitis-associated colorectal cancer in mice

Cellular & Molecular Immunology volume 13, pages 688–699 (2016)Cite this article

Abstract

Inflammatory bowel disease (IBD) is an important factor in the induction of colon cancer, but its mechanism is unclear. Colitis and colitis-associated colorectal cancer (CAC) models induced using both dextran sulfate sodium (DSS) and the azoxymethane/DSS protocol were established in wild-type (WT) and CTRP4 transgenic (CTRP4-tg) C57BL6/J mice. Body weight, stool consistency and the presence of blood in the stool were analyzed; tumor quantity, size and histological characteristics were analyzed during the development of CAC. The CTRP4-tg mice exhibited significantly reduced colitis and developed far fewer macroscopic tumors; these tumors were smaller in size, and a majority of the colon tumors in these mice were restricted to the superficial mucosa. Tumors of lower grades were observed in the CTRP4-tg mice. Interleukin-6 was markedly downregulated in the CTRP4-tg mice during CAC tumorigenesis. The phosphorylation of ERK, signal transducer and activator of transcription 3 and Akt in the colon and the proliferation of intestinal epithelial cells were decreased in the CTRP4-tg mice. The injection of recombinant CTRP4 protein significantly reduced the colitis symptoms of the WT mice. CTRP4 plays an important role in inflammation and inflammation-associated colon tumorigenesis, and our research may provide a novel method for the treatment of IBD and CAC.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Abraham C, Cho JH . Inflammatory bowel disease. N Engl J Med 2009; 361: 2066–2078.

    Article  CAS  Google Scholar 

  2. Kaser A, Zeissig S, Blumberg RS . Inflammatory bowel disease. Annu Rev Immunol 2010; 28: 573–621.

    Article  CAS  Google Scholar 

  3. Abraham C, Cho JH . IL-23 and autoimmunity: new insights into the pathogenesis of inflammatory bowel disease. Annu Rev Med 2009; 60: 97–110.

    Article  CAS  Google Scholar 

  4. Gillen CD, Walmsley RS, Prior P, Andrews HA, Allan RN . Ulcerative colitis and Crohn’s disease: a comparison of the colorectal cancer risk in extensive colitis. Gut 1994; 35: 1590–1592.

    Article  CAS  Google Scholar 

  5. Popivanova BK, Kitamura K, Wu Y, Kondo T, Kagaya T, Kaneko S et al. Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis. J Clin Invest 2008; 118: 560–570.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Grivennikov S, Karin E, Terzic J, Mucida D, Yu GY, Vallabhapurapu S et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 2009; 15: 103–113.

    Article  CAS  Google Scholar 

  7. Gao SP, Mark KG, Leslie K, Pao W, Motoi N, Gerald WL et al. Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J Clin Invest 2007; 117: 3846–3856.

    Article  CAS  Google Scholar 

  8. Li Q, Wang L, Tan W, Peng Z, Luo Y, Zhang Y et al. Identification of C1qTNF-related protein 4 as a potential cytokine that stimulates the STAT3 and NF-kappaB pathways and promotes cell survival in human cancer cells. Cancer Lett 2011; 308: 203–214.

    Article  CAS  Google Scholar 

  9. Atreya R, Neurath MF . Involvement of IL-6 in the pathogenesis of inflammatory bowel disease and colon cancer. Clin Rev Allergy Immunol 2005; 28: 187–196.

    Article  CAS  Google Scholar 

  10. Strober W, Fuss I, Mannon P . The fundamental basis of inflammatory bowel disease. J Clin Invest 2007; 117: 514–521.

    Article  CAS  Google Scholar 

  11. Becker C, Fantini MC, Schramm C, Lehr HA, Wirtz S, Nikolaev A et al. TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling. Immunity 2004; 21: 491–501.

    Article  CAS  Google Scholar 

  12. Dann SM, Spehlmann ME, Hammond DC, Iimura M, Hase K, Choi LJ et al. IL-6-dependent mucosal protection prevents establishment of a microbial niche for attaching/effacing lesion-forming enteric bacterial pathogens. J Immunol 2008; 180: 6816–6826.

    Article  CAS  Google Scholar 

  13. Atreya R, Mudter J, Finotto S, Mullberg J, Jostock T, Wirtz S et al. Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in crohn disease and experimental colitis in vivo. Nat Med 2000; 6: 583–588.

    Article  CAS  Google Scholar 

  14. Heikkila K, Ebrahim S, Lawlor DA . Systematic review of the association between circulating interleukin-6 (IL-6) and cancer. Eur J Cancer 2008; 44: 937–945.

    Article  CAS  Google Scholar 

  15. Schaffler A, Buechler C . CTRP family: linking immunity to metabolism. Trends Endocrinol Metab 2012; 23: 194–204.

    Article  Google Scholar 

  16. Wong GW, Wang J, Hug C, Tsao TS, Lodish HF . A family of Acrp30/adiponectin structural and functional paralogs. Proc Natl Acad Sci USA 2004; 101: 10302–10307.

    Article  CAS  Google Scholar 

  17. Jeon JH, Kim KY, Kim JH, Baek A, Cho H, Lee YH et al. A novel adipokine CTRP1 stimulates aldosterone production. FASEB J 2008; 22: 1502–1511.

    Article  CAS  Google Scholar 

  18. Wong GW, Krawczyk SA, Kitidis-Mitrokostas C, Revett T, Gimeno R, Lodish HF . Molecular, biochemical and functional characterizations of C1q/TNF family members: adipose-tissue-selective expression patterns, regulation by PPAR-gamma agonist, cysteine-mediated oligomerizations, combinatorial associations and metabolic functions. Biochem J 2008; 416: 161–177.

    Article  CAS  Google Scholar 

  19. Kopp A, Bala M, Buechler C, Falk W, Gross P, Neumeier M et al. C1q/TNF-related protein-3 represents a novel and endogenous lipopolysaccharide antagonist of the adipose tissue. Endocrinology 2010; 151: 5267–5278.

    Article  CAS  Google Scholar 

  20. Compton SA, Cheatham B . CTRP-3: blocking a toll booth to obesity-related inflammation. Endocrinology 2010; 151: 5095–5097.

    Article  CAS  Google Scholar 

  21. Wong GW, Krawczyk SA, Kitidis-Mitrokostas C, Ge G, Spooner E, Hug C et al. Identification and characterization of CTRP9, a novel secreted glycoprotein, from adipose tissue that reduces serum glucose in mice and forms heterotrimers with adiponectin. FASEB J 2009; 23: 241–258.

    Article  CAS  Google Scholar 

  22. Byerly MS, Petersen PS, Ramamurthy S, Seldin MM, Lei X, Provost E et al. C1q/TNF-related protein 4 (CTRP4) is a unique secreted protein with two tandem C1q domains that functions in the hypothalamus to modulate food intake and body weight. J Biol Chem 2014; 289: 4055–4069.

    Article  CAS  Google Scholar 

  23. Cooper HS, Murthy SN, Shah RS, Sedergran DJ . Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab Invest 1993; 69: 238–249.

    CAS  PubMed  Google Scholar 

  24. Stopfer P, Obermeier F, Dunger N, Falk W, Farkas S, Janotta M et al. Blocking lymphotoxin-beta receptor activation diminishes inflammation via reduced mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expression and leucocyte margination in chronic DSS-induced colitis. Clin Exp Immunol 2004; 136: 21–29.

    Article  CAS  Google Scholar 

  25. Na D, Ma Z, Luo Y, Li Q, Tan W, Wang L et al. Establishment of adipocytokine CTRP4 transgenic mouse. Chin J Comp Med 2014; 24: 7.

    Google Scholar 

  26. Li B, Alli R, Vogel P, Geiger TL . IL-10 modulates DSS-induced colitis through a macrophage-ROS-NO axis. Mucosal Immunol 2013; 7: 869–878.

    Article  Google Scholar 

  27. Sugimoto K, Ogawa A, Mizoguchi E, Shimomura Y, Andoh A, Bhan AK et al. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J Clin Invest 2008; 118: 534–544.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Ahern PP, Schiering C, Buonocore S, McGeachy MJ, Cua DJ, Maloy KJ et al. Interleukin-23 drives intestinal inflammation through direct activity on T cells. Immunity 2010; 33: 279–288.

    Article  CAS  Google Scholar 

  29. Putoczki TL, Thiem S, Loving A, Busuttil RA, Wilson NJ, Ziegler PK et al. Interleukin-11 is the dominant IL-6 family cytokine during gastrointestinal tumorigenesis and can be targeted therapeutically. Cancer Cell 2013; 24: 257–271.

    Article  CAS  Google Scholar 

  30. Wang W, Li T, Wang X, Yuan W, Cheng Y, Zhang H et al. FAM19A4 is a novel cytokine ligand of formyl peptide receptor 1 (FPR1) and is able to promote the migration and phagocytosis of macrophages. Cell Mol Immunol 2015; 12: 615–624.

    Article  Google Scholar 

  31. Antonioli L, Blandizzi C, Pacher P, Hasko G . Immunity, inflammation and cancer: a leading role for adenosine. Nat Rev Cancer 2013; 13: 842–857.

    Article  CAS  Google Scholar 

  32. Grivennikov SI, Greten FR, Karin M . Immunity, inflammation, and cancer. Cell 2010; 140: 883–899.

    Article  CAS  Google Scholar 

  33. Gupta J, del Barco Barrantes I, Igea A, Sakellariou S, Pateras IS, Gorgoulis VG et al. Dual function of p38alpha MAPK in colon cancer: suppression of colitis-associated tumor initiation but requirement for cancer cell survival. Cancer Cell 2014; 25: 17.

    Article  Google Scholar 

  34. Grivennikov SI, Wang K, Mucida D, Stewart CA, Schnabl B, Jauch D et al. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature 2012; 491: 254–258.

    Article  CAS  Google Scholar 

  35. Bollrath J, Phesse TJ, von Burstin VA, Putoczki T, Bennecke M, Bateman T et al. gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell 2009; 15: 91–102.

    Article  CAS  Google Scholar 

  36. Kishimoto T . Interleukin-6: from basic science to medicine—40 years in immunology. Annu Rev Immunol 2005; 23: 1–21.

    Article  CAS  Google Scholar 

  37. Fu XY . STAT3 in immune responses and inflammatory bowel diseases. Cell Res 2006; 16: 214–219.

    Article  CAS  Google Scholar 

  38. Schenk M, Bouchon A, Seibold F, Mueller C . TREM-1—expressing intestinal macrophages crucially amplify chronic inflammation in experimental colitis and inflammatory bowel diseases. J Clin Invest 2007; 117: 3097–3106.

    Article  CAS  Google Scholar 

  39. Greten FR, Eckmann L, Greten TF, Park JM, Li ZW, Egan LJ et al. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 2004; 118: 285–296.

    Article  CAS  Google Scholar 

  40. Cox JH, Kljavin NM, Ota N, Leonard J, Roose-Girma M, Diehl L et al. Opposing consequences of IL-23 signaling mediated by innate and adaptive cells in chemically induced colitis in mice. Mucosal Immunol 2012; 5: 99–109.

    Article  CAS  Google Scholar 

  41. Greten FR, Eckmann L, Greten TF, Park JM, Li ZW, Egan LJ et al. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 2004; 118: 285–296.

    Article  CAS  Google Scholar 

  42. Arranz A, Doxaki C, Vergadi E, Martinez de la Torre Y, Vaporidi K, Lagoudaki ED et al. Akt1 and Akt2 protein kinases differentially contribute to macrophage polarization. Proc Natl Acad Sci USA 2012; 109: 9517–9522.

    Article  CAS  Google Scholar 

  43. Ohashi K, Parker JL, Ouchi N, Higuchi A, Vita JA, Gokce N et al. Adiponectin promotes macrophage polarization toward an anti-inflammatory phenotype. J Biol Chem 2010; 285: 6153–6160.

    Article  CAS  Google Scholar 

  44. Lin Y, Yang X, Yue W, Xu X, Li B, Zou L et al. Chemerin aggravates DSS-induced colitis by suppressing M2 macrophage polarization. Cell Mol Immunol 2014; 11: 355–366.

    Article  CAS  Google Scholar 

  45. Sarra M, Pallone F, Macdonald TT, Monteleone G . IL-23/IL-17 axis in IBD. Inflamm Bowel Dis 2010; 16: 1808–1813.

    Article  Google Scholar 

  46. Zhao J, Zhang Z, Luan Y, Zou Z, Sun Y, Li Y et al. Pathological functions of interleukin-22 in chronic liver inflammation and fibrosis with hepatitis B virus infection by promoting T helper 17 cell recruitment. Hepatology 2014; 59: 1331–1342.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Xiaoyan Qiu for assistance with the H&E staining and histological analysis and Dalong Ma for insightful discussion and suggestions. This work was supported by grants from the National Natural Science Foundation of China (No. 91129707, No. 81172001).

Author information

Author notes

  1. Yang Luo and Xiaotong Wu: These authors contributed equally to the article.

Authors and Affiliations

  1. Department of Immunology, Key Laboratory of Medical Immunology (Ministry of Health), School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China

    Yang Luo, Xiaotong Wu, Zhuang Ma, Weifeng Tan, Lanlan Wang, Daxiang Na, Guoying Zhang, Ang Yin, He Huang, Dan Xia, Yingmei Zhang & Lu Wang

  2. Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China

    Xueying Shi

Authors
  1. Yang Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaotong Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhuang Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Weifeng Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lanlan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Daxiang Na
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Guoying Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ang Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. He Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Dan Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yingmei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Xueying Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Lu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lu Wang.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Luo, Y., Wu, X., Ma, Z. et al. Expression of the novel adipokine C1qTNF-related protein 4 (CTRP4) suppresses colitis and colitis-associated colorectal cancer in mice. Cell Mol Immunol 13, 688–699 (2016). https://doi.org/10.1038/cmi.2016.16

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cmi.2016.16

Keywords

This article is cited by

Search

Advanced search

Quick links