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Gene alteration of intestinal intraepithelial lymphocytes in response to massive small bowel resection

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Abstract

Background

The intestinal adaptive response [increased epithelial cell (EC) proliferation and apoptosis] after massive small bowel resection (SBR) is partially controlled by intraepithelial lymphocytes (IEL). To identify IEL factors contributing to EC adaptation post-SBR we utilized microarray assays.

Methods

Mice underwent a 70% SBR (SBR1w/SBR4w) or sham operation (Sham1w/Sham4w). After 1 or 4 weeks (1w, 4w) small bowel was harvested, and IEL isolated. Determination of the EC-proliferation rate used BrdU incorporation, and of the EC-apoptotic rate used Annexin V staining. Affymetrix system microarrays (12,491 genes) were performed to examine IEL-mRNA expression. Results were considered significant if fold-change (FC) between groups was >2 and P <0.05 (F-test), or FC>3 and 0.05> P >0.01, or FC>4 and P >0.05. Significant genes were confirmed by conventional RT-PCR.

Results

The SBR EC-proliferation rate increased significantly in both 1w and 4w groups compared to Sham: SBR1w 0.24±0.07 vs. Sham1w 0.12±0.02 ( P =0.03); SBR4w 0.35±0.04 vs. Sham4w 0.19±0.02 ( P <0.01). The EC-apoptotic rate was unchanged in the 1w group, but significantly differed from controls after 4 weeks: SBR4w 39.92±6.78 vs. Sham4w 12.56±6.44 ( P <0.01). Microarray results were analyzed to identify potential growth-modifying IEL genes. The following were identified (function in parenthesis; A, apoptosis; P, proliferation): lipocalin 2 (promotes A), angiotensin converting enzyme (increases A), Rap2 interacting protein (reduces A, promotes P), amphiregulin (promotes P) and leucine-rich-α2-glycoprotein (promotes A, reduces P). Based on RT-PCR results these genes showed significant changes between groups. The increase in ACE at 1w preceded the observed apoptotic changes. The alterations in lipocalin 2, Rap2 and amphiregulin at 4w coincided with the marked changes in growth and apoptosis in the SBR mice.

Conclusions

IEL undergo temporal changes after SBR. These findings provide profound insight into potential IEL-dependent regulation of EC homeostasis post-SBR.

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References

  1. Beagley KW, Husband AJ (1998) Intraepithelial lymphocytes: origins, distribution, and function. Crit Rev Immunol 18:237–254

    CAS  PubMed  Google Scholar 

  2. Guy-Grand D, Di Santo JP, Henchoz P, Malassis-Seris M, Vassalli P (1998) Small bowel enteropathy: role of intraepithelial lymphocytes and of cytokines (IL-12, IFN-gamma, TNF) in the induction of epithelial cell death and renewal. Eur J Immunol 28:730–744

    Google Scholar 

  3. Eisenbraun MD, Mosley RL, Teitelbaum DH, Miller RA (2000) Altered development of intestinal intraepithelial lymphocytes in p-glycoprotein-deficient mice. Dev Comp Immunol 24:783–795

    Article  CAS  PubMed  Google Scholar 

  4. Helmrath MA, VanderKolk WE, Can G, Erwin CR, Warner BW (1996) Intestinal adaptation following massive small bowel resection in the mouse. J Am Coll Surg 183:441–449

    CAS  PubMed  Google Scholar 

  5. Kiristioglu I, Teitelbaum DH (1998) Alteration of the intestinal intraepithelial lymphocytes during total parenteral nutrition. J Surg Res 79:91–96

    PubMed  Google Scholar 

  6. Welters CF, Dejong CH, Deutz NE, Heineman E (2002) Intestinal adaptation in short bowel syndrome. ANZ J Surg 72:229–236

    Article  PubMed  Google Scholar 

  7. Falcone RA Jr, Stern LE, Kemp CJ, Shin CE, Erwin CR, Warner BW (1999) Apoptosis and the pattern of DNase I expression following massive small bowel resection. J Surg Res 84:218–222

  8. Klein RM, McKenzie JC (1983) The role of cell renewal in the ontogeny of the intestine. J Pediatr Gastroenterol Nutr 2:204–228

    CAS  PubMed  Google Scholar 

  9. Iwakiri D, Podolsky DK (2001) Keratinocyte growth factor promotes goblet cell differentiation through regulation of goblet cell silencer inhibitor. Gastroenterology 120:1372–1380

    CAS  PubMed  Google Scholar 

  10. Boismenu R, Havran WL (1994) Modulation of epithelial cell growth by intraepithelial gamma delta T cells. Science 266:1253–1255

    CAS  PubMed  Google Scholar 

  11. Barrett T, Gajewski T, Danielpour D, Chang E, Beagley K, Bluestone J (1992) Differential function of intestinal intraepithelial lymphocyte subsets. J Immunol 149:1124–1130

    PubMed  Google Scholar 

  12. Abreu-Martin MT, Palladino AA, Faris M, Carramanzana NM, Nel AE, Targan SR (1999) Fas activates the JNK pathway in human colonic epithelial cells: lack of a direct role in apoptosis. Am J Physiol 276: G599–605

    PubMed  Google Scholar 

  13. Flower DR (1996) The lipocalin protein family: structure and function. Biochem J 318:1–14

    CAS  PubMed  Google Scholar 

  14. Devireddy LR, Teodoro JG, Richard FA, Green MR (2001) Induction of apoptosis by a secreted lipocalin that is transcriptionally regulated by IL-3 deprivation. Science 293:829–834

    Article  CAS  PubMed  Google Scholar 

  15. Janoueix-Lerosey I, Pasheva E, de Tand MF, Tavitian A, de Gunzburg J (1998) Identification of a specific effector of the small GTP-binding protein Rap2. Eur J Biochem 252:290–298

    Article  CAS  PubMed  Google Scholar 

  16. Janda E, Litos G, Grunert S, Downward J, Beug H (2002) Oncogenic Ras/Her-2 mediate hyperproliferation of polarized epithelial cells in 3D cultures and rapid tumor growth via the PI3 K pathway. Oncogene 21:5148–5159

    Article  CAS  PubMed  Google Scholar 

  17. Danielsen AJ, Maihle NJ (2002) The EGF/ErbB receptor family and apoptosis. Growth Factors 20:1–15

    Article  CAS  PubMed  Google Scholar 

  18. Nancy V, Wolthuis RM, de Tand MF, Janoueix-Lerosey I, Bos JL, de Gunzburg J (1999) Identification and characterization of potential effector molecules of the Ras-related GTPase Rap2. J Biol Chem 274:8737–8745

    Article  CAS  PubMed  Google Scholar 

  19. Jimenez B, Pizon V, Lerosey I, Beranger F, Tavitian A, de Gunzburg J (1991) Effects of the Ras-related Rap2 protein on cellular proliferation. Int J Cancer 49:471–479

    CAS  PubMed  Google Scholar 

  20. Sehgal I, Bailey J, Hitzemann K, Pittelkow MR, Maihle NJ (1994) Epidermal growth factor receptor-dependent stimulation of amphiregulin expression in androgen-stimulated human prostate cancer cells. Mol Biol Cell 5:339–347

    CAS  PubMed  Google Scholar 

  21. Li S, Plowman GD, Buckley SD, Shipley GD (1992) Heparin inhibition of autonomous growth implicates amphiregulin as an autocrine growth factor for normal human mammary epithelial cells. J Cell Physiol 153:103–111

    CAS  PubMed  Google Scholar 

  22. Johnson GR, Saeki T, Gordon AW, Shoyab M, Salomon DS, Stromberg K (1992) Autocrine action of amphiregulin in a colon carcinoma cell line and immunocytochemical localization of amphiregulin in human colon. J Cell Biol 118:741–751

    CAS  PubMed  Google Scholar 

  23. Silvy M, Giusti C, Martin PM, Berthois Y (2001) Differential regulation of cell proliferation and protease secretion by epidermal growth factor and amphiregulin in tumoral versus normal breast epithelial cells. Br J Cancer 84:936–945

    Article  CAS  PubMed  Google Scholar 

  24. Luetteke NC, Qiu TH, Fenton SE, Troyer KL, Riedel RF, Chang A, Lee DC (1999) Targeted inactivation of the EGF and amphiregulin genes reveals distinct roles for EGF receptor ligands in mouse mammary gland development. Development 126:2739–2750

    CAS  PubMed  Google Scholar 

  25. Dunker N, Schmitt K, Schuster N, Krieglstein K (2002) The role of transforming growth factor beta-2, beta-3 in mediating apoptosis in the murine intestinal mucosa. Gastroenterology 122:1364–1375

    PubMed  Google Scholar 

  26. Dignass AU, Sturm A (2001) Peptide growth factors in the intestine. Eur J Gastroenterol Hepatol 13:763–770

    Article  CAS  PubMed  Google Scholar 

  27. Wang R, Zagariya A, Ibarra-Sunga O, Gidea C, Ang E, Deshmukh S, Chaudhary G, Baraboutis J, Filippatos G, Uhal BD (1999) Angiotensin II induces apoptosis in human and rat alveolar epithelial cells. Am J Physiol 276:L885–889

    CAS  PubMed  Google Scholar 

  28. Kajstura J, Cigola E, Malhotra A, Li P, Cheng W, Meggs LG, Anversa P (1997) Angiotensin II induces apoptosis of adult ventricular myocytes in vitro. J Mol Cell Cardiol 29:859–870

    Article  CAS  PubMed  Google Scholar 

  29. Dimmeler S, Rippmann V, Weiland U, Haendeler J, Zeiher AM (1997) Angiotensin II induces apoptosis of human endothelial cells. Protective effect of nitric oxide. Circ Res 81:970–976

    CAS  PubMed  Google Scholar 

  30. Schindler R, Dinarello CA, Koch KM (1995) Angiotensin-converting-enzyme inhibitors suppress synthesis of tumour necrosis factor and interleukin 1 by human peripheral blood mononuclear cells. Cytokine 7:526–533

    Article  CAS  PubMed  Google Scholar 

  31. Constantinescu CS, Goodman DB, Ventura ES (1998) Captopril and lisinopril suppress production of interleukin-12 by human peripheral blood mononuclear cells. Immunol Lett 62:25–31

    Article  CAS  PubMed  Google Scholar 

  32. Kono Y, Sawada S, Kawahara T, Tsuda Y, Higaki T, Yamasaki S, Imamura H, Tada Y, Sato T, Hiranuma O, Akamatsu N, Komatsu S, Tamagaki T, Nakagawa K, Tsuji H, Nakagawa M (2002) Bradykinin inhibits serum-depletion-induced apoptosis of human vascular endothelial cells by inducing nitric oxide via calcium ion kinetics. J Cardiovasc Pharmacol 39:251–261

    Article  CAS  PubMed  Google Scholar 

  33. Yoshida H, Zhang JJ, Chao L, Chao J (2000) Kallikrein gene delivery attenuates myocardial infarction and apoptosis after myocardial ischemia and reperfusion. Hypertension 35:25–31

    CAS  PubMed  Google Scholar 

  34. Uhal BD, Gidea C, Bargout R, Bifero A, Ibarra-Sunga O, Papp M, Flynn K, Filippatos G (1998) Captopril inhibits apoptosis in human lung epithelial cells: a potential antifibrotic mechanism. Am J Physiol 275:L1013–1017

    CAS  PubMed  Google Scholar 

  35. Odaka C, Mizuochi T (2000) Angiotensin-converting enzyme inhibitor captopril prevents activation-induced apoptosis by interfering with T cell activation signals. Clin Exp Immunol 121:515–522

    Article  CAS  PubMed  Google Scholar 

  36. Yu G, Liang X, Xie X, Su M, Zhao S (2001) Diverse effects of chronic treatment with losartan, fosinopril, and amlodipine on apoptosis, angiotensin II in the left ventricle of hypertensive rats. Int J Cardiol 81:123–129

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by a grant from the National Institute of Health, USA (AI44076–01), by fellowships from Novartis Stiftung Schweiz, Swiss National Foundation, and the Swiss Society of Pediatric Surgery. Microarray analysis was supported through the University of Michigan NIDDK Biotechnology Center.

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Authors and Affiliations

  1. Department of Surgery, Section of Pediatric Surgery, C.S. Mott Children's Hospital, University of Michigan, Mott F3970, Box 0245, Ann Arbor, Michigan, 48109, USA

    Barbara E. Wildhaber, Hua Yang, Arnold G. Coran & Daniel H. Teitelbaum

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  1. Barbara E. Wildhaber
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  2. Hua Yang
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  3. Arnold G. Coran
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  4. Daniel H. Teitelbaum
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Correspondence to Daniel H. Teitelbaum.

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Wildhaber, B.E., Yang, H., Coran, A.G. et al. Gene alteration of intestinal intraepithelial lymphocytes in response to massive small bowel resection. Ped Surgery Int 19, 310–315 (2003). https://doi.org/10.1007/s00383-003-1001-x

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