Molecular Medicine

, Volume 17, Issue 5–6, pp 502–507 | Cite as

Milk Fat Globule-EGF Factor 8 Is a Critical Protein for Healing of Dextran Sodium Sulfate-Induced Acute Colitis in Mice

  • Ashish Chogle
  • Heng-Fu Bu
  • Xiao Wang
  • Jeffrey B Brown
  • Pauline M Chou
  • Xiao-Di Tan
Research Article


Milk fat globule-EGF factor 8 (MFG-E8) has been shown to play an important role in maintaining the integrity of the intestinal mucosa and to accelerate healing of the mucosa in septic mice. Herein, we (a) analyzed the expression of MFG-E8 in the gut of wild-type (WT) C57BL/6 (MFG-E8+/+) mice with and without dextran sulfate sodium (DSS)-induced colitis, (b) characterized the pathological changes in intestinal mucosa of MFG-E8+/+ and MFG-E8-/- mice with DSS-induced colitis and (c) examined the therapeutic role of MFG-E8 in inflammatory bowel disease by using DSS-induced colitis model. Our data documented that there was an increase in colonic and rectal MFG-E8 expression in MFG-E8+/+ mice during the development of DSS colitis. MFG-E8 levels in both tissues decreased to below baseline during the recovery phase in mice with colitis. Changes in MFG-E8 gene expression correlated to the levels of inflammatory response and crypt-epithelial injury in both colonic and rectal mucosa in MFG-E8+/+ mice. MFG-E8-/- mice developed more severe crypt-epithelial injury than MFG-E8+/+ mice during exposure to DSS with delayed healing of intestinal epithelium during the recovery phase of DSS colitis. Administration of MFG-E8 during the recovery phase ameliorated colitis and promoted mucosal repair in both MFG-E8-/- and MFG-E8+/+ mice, indicating that lack of MFG-E8 causes increased susceptibility to colitis and delayed mucosal healing. These data suggest that MGF-E8 is an essential protective factor for gut epithelial homeostasis, and exogenous administration of MFG-E8 may represent a novel therapeutic target in inflammatory bowel disease.



This work was supported in part by the Grant R01DK064240 (to X-D Tan) from National Institutes of Health, the Excellence in Academic Medicine Award from Illinois Department of Public Aid (to X-D Tan) and Eloise and Warren Batts Investigator Chair (to X-D Tan). We thank Barry D Shur (Emory University School of Medicine) for MFG-E8 deficient mouse colony.

Supplementary material

10020_2011_1705502_MOESM1_ESM.pdf (524 kb)
Milk Fat Globule-EGF Factor 8 Is a Critical Protein for Healing of Dextran Sodium Sulfate-Induced Acute Colitis in Mice


  1. 1.
    Podolsky DK. (2002) Inflammatory bowel disease. N. Engl. J. Med. 347:417–29.CrossRefGoogle Scholar
  2. 2.
    Yu Y, Sitaraman S, Gewirtz AT. (2004) Intestinal epithelial cell regulation of mucosal inflammation. Immunol. Res. 29:55–68.CrossRefGoogle Scholar
  3. 3.
    Zhao D, et al. (2006) Ghrelin stimulates interleukin-8 gene expression through protein kinase C-mediated NF-kappaB pathway in human colonic epithelial cells. J. Cell. Biochem. 97:1317–27.CrossRefGoogle Scholar
  4. 4.
    Talero E, Sanchez-Fidalgo S, Ramon CJ, Motilva V. (2006) Galanin in the trinitrobenzene sulfonic acid rat model of experimental colitis. Int. Immunopharmacol. 6:1404–12.CrossRefGoogle Scholar
  5. 5.
    Talero E, Sanchez-Fidalgo S, Calvo JR, Motilva V. (2007) Chronic administration of galanin attenuates the TNBS-induced colitis in rats. Regul. Pept. 141:96–104.CrossRefGoogle Scholar
  6. 6.
    Pentney PT, Bubenik GA. (1995) Melatonin reduces the severity of dextran-induced colitis in mice. J. Pineal Res. 19:31–9.CrossRefGoogle Scholar
  7. 7.
    Kojima M, Kangawa K. (2006) Drug insight: the functions of ghrelin and its potential as a multitherapeutic hormone. Nat. Clin. Pract. Endocrinol. Metab. 2:80–8.CrossRefGoogle Scholar
  8. 8.
    Kojima M, et al. (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 402:656–60.CrossRefGoogle Scholar
  9. 9.
    Dong WG, et al. (2003) Effects of melatonin on the expression of iNOS and COX-2 in rat models of colitis. World J. Gastroenterol. 9:1307–11.CrossRefGoogle Scholar
  10. 10.
    Cuzzocrea S, et al. (2001) Melatonin reduces dinitrobenzene sulfonic acid-induced colitis. J. Pineal Res. 30:1–12.CrossRefGoogle Scholar
  11. 11.
    Ashizuka S, et al. (2005) Effect of adrenomedullin administration on acetic acid-induced colitis in rats. Peptides. 26:2610–5.CrossRefGoogle Scholar
  12. 12.
    Abad C, et al. (2003) Therapeutic effects of vasoactive intestinal peptide in the trinitrobenzene sulfonic acid mice model of Crohn’s disease. Gastroenterology. 124:961–71.CrossRefGoogle Scholar
  13. 13.
    Abad C, et al. (2005) cDNA array analysis of cytokines, chemokines, and receptors involved in the development of TNBS-induced colitis: homeostatic role of VIP. Inflamm. Bowel. Dis. 11:674–84.CrossRefGoogle Scholar
  14. 14.
    Stubbs JD, et al. (1990) cDNA cloning of a mouse mammary epithelial cell surface protein reveals the existence of epidermal growth factor-like domains linked to factor VIII-like sequences. Proc. Natl. Acad. Sci. U.S.A. 87:8417–21.CrossRefGoogle Scholar
  15. 15.
    Yolken RH, et al. (1992) Human milk mucin inhibits rotavirus replication and prevents experimental gastroenteritis. J. Clin. Invest. 90:1984–91.CrossRefGoogle Scholar
  16. 16.
    Oshima K, et al. (1999) Lactation-dependent expression of an mRNA splice variant with an exon for a multiply O-glycosylated domain of mouse milk fat globule glycoprotein MFG-E8. Biochem. Biophys. Res. Commun. 254:522–8.CrossRefGoogle Scholar
  17. 17.
    Wang X, Bu HF, De Plaen IG, Tan XD. (2009) Milk fat globule-EGF factor 8 mRNA expression in rat splanchnic tissues during postnatal development. Intl. J. Clin. Exp. Med. 2:36–40.Google Scholar
  18. 18.
    Bu HF, et al. (2007) Milk fat globule-EGF factor 8/ lactadherin plays a crucial role in maintenance and repair of murine intestinal epithelium. J. Clin. Invest. 117:3673–83.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Aziz MM, et al. (2009) MFG-E8 attenuates intestinal inflammation in murine experimental colitis by modulating osteopontin-dependent alphavbeta3 integrin signaling. J. Immunol. 182:7222–32.CrossRefGoogle Scholar
  20. 20.
    Ensslin MA, Shur BD. (2003) Identification of mouse sperm SED1, a bimotif EGF repeat and discoidin-domain protein involved in sperm-egg binding. Cell. 114:405–17.CrossRefGoogle Scholar
  21. 21.
    Krieglstein CF, et al. (2007) Role of blood- and tissue-associated inducible nitric-oxide synthase in colonic inflammation. Am. J. Pathol. 170:490–6.CrossRefGoogle Scholar
  22. 22.
    Bu HF, et al. (2006) Lysozyme-modified probiotic components protect rats against polymicrobial sepsis: role of macrophages and cathelicidinrelated innate immunity. J. Immunol. 177:8767–76.CrossRefGoogle Scholar
  23. 23.
    Livak KJ, Schmittgen TD. (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 25:402–8.CrossRefGoogle Scholar
  24. 24.
    Cui T, et al. (2009) Milk fat globule epidermal growth factor 8 attenuates acute lung injury in mice after intestinal ischemia and reperfusion. Am. J. Respir. Crit. Care Med. 181:238–46.CrossRefGoogle Scholar
  25. 25.
    Atabai K, et al. (2009) Mfge8 diminishes the severity of tissue fibrosis in mice by binding and targeting collagen for uptake by macrophages. J. Clin. Invest. 119:3713–22.CrossRefGoogle Scholar

Copyright information

© The Feinstein Institute for Medical Research 2011

Authors and Affiliations

  • Ashish Chogle
    • 1
    • 2
  • Heng-Fu Bu
    • 2
  • Xiao Wang
    • 2
  • Jeffrey B Brown
    • 1
    • 2
  • Pauline M Chou
    • 3
  • Xiao-Di Tan
    • 1
    • 2
    • 3
  1. 1.Division of Gastroenterology and Hepatology, Department of Pediatrics, Feinberg School of MedicineNorthwestern UniversityChicagoUSA
  2. 2.Center for Intestinal and Liver Inflammation Research, Children’s Memorial Research Center, Children’s Memorial Hospital Feinberg School of MedicineNorthwestern UniversityChicagoUSA
  3. 3.Department of Pathology, Feinberg School of MedicineNorthwestern UniversityChicagoUSA

Personalised recommendations