Skip to main content

Advertisement

SpringerLink
Log in

Duodenal Expression of Toll-Like Receptors and Interleukins Are Increased in Both Children and Adult Celiac Patients

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Background

Toll-like receptors (TLRs) have achieved an extraordinary amount of interest in inflammatory diseases due to their role in the inflammatory activation. By activating the production of several biological factors, TLRs induce type I interferons and other cytokines, which drive the inflammatory response and activate the adaptive immune system.

Aims

The aim of this study was to investigate and compare the expression and clinical relevance of TLRs and interleukins in pediatric and adult celiac disease (CD), defined as intolerance to dietary proteins found in wheat, barley, and rye.

Methods

The expression levels of TLR3, TLR4, and TLR7, interleukins, and different transcription factors were analyzed on duodenal biopsies from ten children and 31 adults with CD, and 21 duodenal controls biopsies without CD (ten children and 11 adults). The analyses were performed by immunohistochemistry and real-time PCR.

Results

There were no significant differences in the studied parameters between adults and children. TLR4 expression level was increased twofold in CD specimens compared to controls. CD patients with high levels of TLR4 also showed high levels of interleukins (IL1, IL6, IL8, and IL17) as well as transcription factors (IRAK4, MyD88, and NF-κB).

Conclusions

TLR4 expression is associated with CD independently of age at diagnosis. Pediatric patients and adult patients have a similar inflammatory profile, making it possible to treat both with the same immunological therapy in the future.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Monteleone I, Sarra M, Del Vecchio Blanco G, et al. Characterization of IL-17A-producing cells in celiac disease mucosa. J Immunol. 2010;184:2211–2218.

    Article  PubMed  CAS  Google Scholar 

  2. Sollid LM, Thorsby E. HLA susceptibility genes in celiac disease: genetic mapping and role in pathogenesis. Gastroenterology. 1993;105:910–922.

    PubMed  CAS  Google Scholar 

  3. Setty M, Hormaza L, Guandalini S. Celiac disease: risk assessment, diagnosis, and monitoring. Mol Diagn Ther. 2008;12:289–298.

    Article  PubMed  Google Scholar 

  4. Sollid LM. Molecular basis of celiac disease. Annu Rev Immunol. 2000;18:53–81.

    Article  PubMed  CAS  Google Scholar 

  5. Kilmartin C, Lynch S, Abuzakouk M, et al. Avenin fails to induce a Th1 response in coeliac tissue following in vitro culture. Gut. 2003;52:47–52.

    Article  PubMed  CAS  Google Scholar 

  6. Forsberg G, Hernell O, Melgar S, et al. Paradoxical coexpression of proinflammatory and down-regulatory cytokines in intestinal T cells in childhood celiac disease. Gastroenterology. 2002;123:667–678.

    Article  PubMed  CAS  Google Scholar 

  7. Szebeni B, Veres G, Dezsofi A, et al. Increased mucosal expression of Toll-like receptor (TLR)2 and TLR4 in coeliac disease. J Pediatr Gastroenterol Nutr. 2007;45:187–193.

    Article  PubMed  CAS  Google Scholar 

  8. Szebeni B, Veres G, Dezsofi A, et al. Increased expression of Toll-like receptor (TLR) 2 and TLR4 in the colonic mucosa of children with inflammatory bowel disease. Clin Exp Immunol. 2008;151:34–41.

    Article  PubMed  CAS  Google Scholar 

  9. Akira S. Toll-like receptors and innate immunity. Adv Immunol. 2001;78:1–56.

    Article  PubMed  CAS  Google Scholar 

  10. Marshak-Rothstein A. Toll-like receptors in systemic autoimmune disease. Nat Rev Immunol. 2006;6:823–835.

    Article  PubMed  CAS  Google Scholar 

  11. Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol. 2004;4:499–511.

    Article  PubMed  CAS  Google Scholar 

  12. Shang L, Fukata M, Thirunarayanan N, et al. Toll-like receptor signaling in small intestinal epithelium promotes B-cell recruitment and IgA production in lamina propria. Gastroenterology. 2008;135:529–538.

    Article  PubMed  CAS  Google Scholar 

  13. Pasare C, Medzhitov R. Toll-dependent control mechanisms of CD4 T cell activation. Immunity. 2004;21:733–741.

    Article  PubMed  CAS  Google Scholar 

  14. Takeuchi O, Hoshino K, Kawai T, et al. Differential roles of TLR2 and TLR4 in recognition of Gram-negative and Gram-positive bacterial cell wall components. Immunity. 1999;11:443–451.

    Article  PubMed  CAS  Google Scholar 

  15. Kurt-Jones EA, Popova L, Kwinn L, et al. Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat Immunol. 2000;1:398–401.

    Article  PubMed  CAS  Google Scholar 

  16. Gonzalez-Reyes S, Marin L, Gonzalez L, et al. Study of TLR3, TLR4 and TLR9 in breast carcinomas and their association with metastasis. BMC Cancer. 2010;10:665.

    Article  PubMed  CAS  Google Scholar 

  17. Maiuri L, Ciacci C, Ricciardelli I, et al. Association between innate response to gliadin and activation of pathogenic T cells in coeliac disease. Lancet. 2003;362:30–37.

    Article  PubMed  CAS  Google Scholar 

  18. Schuppan D, Esslinger B, Dieterich W. Innate immunity and coeliac disease. Lancet. 2003;362:3–4.

    Article  PubMed  Google Scholar 

  19. Santin I, Castellanos-Rubio A, Hualde I, et al. Toll-like receptor 4 (TLR4) gene polymorphisms in celiac disease. Tissue Antigens. 2007;70:495–498.

    Article  PubMed  CAS  Google Scholar 

  20. Fernandez-Jimenez N, Castellanos-Rubio A, Plaza-Izurieta L, et al. Analysis of beta-defensin and Toll-like receptor gene copy number variation in celiac disease. Hum Immunol. 2010;71:833–836.

    Article  PubMed  CAS  Google Scholar 

  21. Medzhitov R, Janeway CA Jr. Innate immunity: the virtues of a nonclonal system of recognition. Cell. 1997;91:295–298.

    Article  PubMed  CAS  Google Scholar 

  22. Maiuri L, Picarelli A, Boirivant M, et al. Definition of the initial immunologic modifications upon in vitro gliadin challenge in the small intestine of celiac patients. Gastroenterology. 1996;110:1368–1378.

    Article  PubMed  CAS  Google Scholar 

  23. Sartor RB. Cytokines in intestinal inflammation: pathophysiological and clinical considerations. Gastroenterology. 1994;106:533–539.

    PubMed  CAS  Google Scholar 

  24. Bettelli E, Oukka M, Kuchroo VK. T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol. 2007;8:345–350.

    Article  PubMed  CAS  Google Scholar 

  25. Harris KM, Fasano A, Mann DL. Cutting edge: IL-1 controls the IL-23 response induced by gliadin, the etiologic agent in celiac disease. J Immunol. 2008;181:4457–4460.

    PubMed  CAS  Google Scholar 

  26. Cinova J, Palova-Jelinkova L, Smythies LE, et al. Gliadin peptides activate blood monocytes from patients with celiac disease. J Clin Immunol. 2007;27:201–209.

    Article  PubMed  CAS  Google Scholar 

  27. Jelinkova L, Tuckova L, Cinova J, et al. Gliadin stimulates human monocytes to production of IL-8 and TNF-alpha through a mechanism involving NF-kappaB. FEBS Lett. 2004;571:81–85.

    Article  PubMed  CAS  Google Scholar 

  28. Thomas KE, Sapone A, Fasano A, et al. Gliadin stimulation of murine macrophage inflammatory gene expression and intestinal permeability are MyD88-dependent: role of the innate immune response in Celiac disease. J Immunol. 2006;176:2512–2521.

    PubMed  CAS  Google Scholar 

  29. Sacre SM, Andreakos E, Kiriakidis S, et al. The Toll-like receptor adaptor proteins MyD88 and Mal/TIRAP contribute to the inflammatory and destructive processes in a human model of rheumatoid arthritis. Am J Pathol. 2007;170:518–525.

    Article  PubMed  CAS  Google Scholar 

  30. Ciccocioppo R, Di Sabatino A, Bauer M, et al. Matrix metalloproteinase pattern in celiac duodenal mucosa. Lab Invest. 2005;85:397–407.

    Article  PubMed  CAS  Google Scholar 

  31. Escaff S, Fernandez JM, Gonzalez LO, et al. Study of matrix metalloproteinases and their inhibitors in prostate cancer. Br J Cancer. 2010;102:922–929.

    Article  PubMed  CAS  Google Scholar 

  32. Del Casar JM, Gonzalez-Reyes S, Gonzalez LO, et al. Expression of metalloproteases and their inhibitors in different histological types of breast cancer. J Cancer Res Clin Oncol. 2010;136:811–819.

    Article  PubMed  Google Scholar 

  33. Altadill A, Rodriguez M, Gonzalez LO, et al. Liver expression of matrix metalloproteases and their inhibitors in hepatocellular carcinoma. Dig Liver Dis. 2009;41:740–748.

    Article  PubMed  CAS  Google Scholar 

  34. Gonzalez LO, Corte MD, Vazquez J, et al. Study of matrix metalloproteinases and their tissue inhibitors in ductal in situ carcinomas of the breast. Histopathology. 2008;53:403–415.

    Article  PubMed  CAS  Google Scholar 

  35. Freeman HJ. Adult celiac disease and its malignant complications. Gut Liver. 2009;3:237–246.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from FICEMU.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Unidad de Investigación, Hospital de Jove, Gijón, Spain

    Noemí Eiró, Salomé González-Reyes, Lucía González, Luis O. González, Antonio Altadill, Alejandro Andicoechea & F. J. Vizoso

  2. Servicio de Anatomía Patológica, Hospital de Jove, Gijón, Spain

    Luis O. González

  3. Servicio de Cirugía General, Hospital de Jove, Avda. Eduardo Castro s/n, 33920, Gijón, Asturias, Spain

    Alejandro Andicoechea & F. J. Vizoso

  4. Servicio de medicina interna, Hospital de Jove, Gijón, Spain

    Antonio Altadill

  5. Servicio de Anatomía Patológica, Hospital Universitario Central de Asturias, Oviedo, Spain

    Manuel F. Fresno-Forcelledo

  6. Servicio de digestivo, Hospital Universitario Central de Asturias, Oviedo, Spain

    Luis Rodrigo-Sáez

Authors
  1. Noemí Eiró
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Salomé González-Reyes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lucía González
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Luis O. González
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Antonio Altadill
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alejandro Andicoechea
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Manuel F. Fresno-Forcelledo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Luis Rodrigo-Sáez
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. F. J. Vizoso
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to F. J. Vizoso.

Additional information

The authors Noemí Eiró and Salomé González-Reyes contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Eiró, N., González-Reyes, S., González, L. et al. Duodenal Expression of Toll-Like Receptors and Interleukins Are Increased in Both Children and Adult Celiac Patients. Dig Dis Sci 57, 2278–2285 (2012). https://doi.org/10.1007/s10620-012-2184-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-012-2184-6

Keywords

Search

Navigation