Digestive Diseases and Sciences

, Volume 62, Issue 9, pp 2348–2356 | Cite as

Activation of NLRP3 Inflammasome in Inflammatory Bowel Disease: Differences Between Crohn’s Disease and Ulcerative Colitis

  • Lazaros-Dimitrios Lazaridis
  • Aikaterini Pistiki
  • Evangelos J. Giamarellos-Bourboulis
  • Marianna Georgitsi
  • Georgia Damoraki
  • Dimitrios Polymeros
  • George D. Dimitriadis
  • Konstantinos Triantafyllou
Original Article

Abstract

Background

NLRP3 inflammasome is a multimolecular cytosol complex that, when activated, contributes to the cleavage of pro-interleukin (IL)-1β to IL-1β.

Aims

To investigate NLRP3 inflammasome activation in inflammatory bowel disease.

Methods

Peripheral blood mononuclear cells from Crohn’s disease (CD), ulcerative colitis (UC) patients and controls were stimulated with LPS in the absence or presence of MSU. After incubation, concentrations of IL-1β, IL-6, and TNFα were measured in cell supernatants and concentration of pro-IL-1β was measured in cell lysates. NLRP3 activation was defined as more than 30% increase in IL-1β production after MSU addition. In separate experiments, PBMCs were lysed for RNA isolation transcripts of IL-, TNFα, NLRP3, and CASP1 were measured by RT-PCR. DNA was isolated from CD patients for ATG16L1 gene genotyping.

Results

NLRP3 inflammasome was activated in 60% of CD patients compared to 28.6% of controls (p = 0.042); no significant difference was detected between UC and controls. Among UC patients, NLRP3 activation was associated (p = 0.008) with long-standing disease (>1.5 years). IL-1β levels were significantly higher in CD patents in comparison with controls (p = 0.032). No difference was detected in the levels of IL-6, TNFα, pro-IL-1β and in the numbers IL-, TNFα, NLRP3, and CASP1 transcripts among groups. IL-1β production was similar between carriers of wild-type and of SNP alleles of the rs2241880.

Conclusions

NLRP3 inflammasome is activated in CD patients and in UC patients with long-standing disease.

Keywords

IBD Crohn’s disease Ulcerative colitis NLRP3 inflammasome ATG16L1 

References

  1. 1.
    Zaki MH, Lamkanfi M, Kanneganti TD. The Nlrp3 inflammasome: contributions to intestinal homeostasis. Trends Immunol. 2011;32:171–179.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol. 2009;27:519–550.CrossRefPubMedGoogle Scholar
  3. 3.
    Aguilera M, Darby T, Melgar S. The complex role of inflammasomes in the pathogenesis of Inflammatory Bowel Diseases—lessons learned from experimental models. Cytokine Growth Factor Rev. 2014;25:715–730.CrossRefPubMedGoogle Scholar
  4. 4.
    Church LD, Cook GP, McDermott MF. Primer: inflammasomes and interleukin 1beta in inflammatory disorders. Nat Clin Pract Rheumatol. 2008;4:34–42.CrossRefPubMedGoogle Scholar
  5. 5.
    Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 2002;10:417–426.CrossRefPubMedGoogle Scholar
  6. 6.
    Mariathasan S, Monack DM. Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation. Nat Rev Immunol. 2007;7:31–40.CrossRefPubMedGoogle Scholar
  7. 7.
    Kanneganti TD, Lamkanfi M, Nunez G. Intracellular NOD-like receptors in host defense and disease. Immunity. 2007;27:549–559.CrossRefPubMedGoogle Scholar
  8. 8.
    Opipari A, Franchi L. Role of inflammasomes in intestinal inflammation and Crohn’s disease. Inflamm Bowel Dis. 2015;21:173–181.CrossRefPubMedGoogle Scholar
  9. 9.
    Shao BZ, Xu ZQ, Han BZ, Su DF, Liu C. NLRP3 inflammasome and its inhibitors: a review. Front Pharmacol. 2015;6:262.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Villani AC, Lemire M, Fortin G, et al. Common variants in the NLRP3 region contribute to Crohn’s disease susceptibility. Nat Genet. 2009;41:71–76.CrossRefPubMedGoogle Scholar
  11. 11.
    Schoultz I, Verma D, Halfvarsson J, et al. Combined polymorphisms in genes encoding the inflammasome components NALP3 and CARD8 confer susceptibility to Crohn’s disease in Swedish men. Am J Gastroenterol. 2009;104:1180–1188.CrossRefPubMedGoogle Scholar
  12. 12.
    Lewis GJ, Massey DC, Zhang H, et al. Genetic association between NLRP3 variants and Crohn’s disease does not replicate in a large UK panel. Inflamm Bowel Dis. 2011;17:1387–1391.CrossRefPubMedGoogle Scholar
  13. 13.
    Van Assche G, Dignass A, Panes J, et al. The second European evidence-based Consensus on the diagnosis and management of Crohn’s disease: Definitions and diagnosis. J Crohn’s Colitis. 2010;4:7–27.CrossRefGoogle Scholar
  14. 14.
    Dignass A, Eliakim R, Magro F, et al. Second European evidence-based Consensus on the diagnosis and management of ulcerative colitis Part 1: Definitions and diagnosis (Spanish version). Rev. Gastroenterol. Mex.. 2014;79:263–289.PubMedGoogle Scholar
  15. 15.
    Peyrin-Biroulet L, Billioud V, D’Haens G, et al. Development of the Paris definition of early Crohn’s disease for disease-modification trials: results of an international expert opinion process. Am J Gastroenterol. 2012;107:1770–1776.CrossRefPubMedGoogle Scholar
  16. 16.
    Seegmiller J, Howell R, Malawista S. The inflammatory reaction of sodium urate. JAMA. 1962;180:469–475.CrossRefGoogle Scholar
  17. 17.
    Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 2001;25:402–408.CrossRefPubMedGoogle Scholar
  18. 18.
    Mylona EE, Mouktaroudi M, Crisan TO, et al. Enhanced interleukin-1beta production of PBMCs from patients with gout after stimulation with Toll-like receptor-2 ligands and urate crystals. Arthritis Res Ther. 2012;14:R158.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Kim JM. Inflammatory bowel diseases and inflammasome. Korean J Gastroenterol. 2011;58:300–310.CrossRefPubMedGoogle Scholar
  20. 20.
    Papadakis KA, Targan SR. Role of cytokines in the pathogenesis of inflammatory bowel disease. Annu Rev Med. 2000;51:289–298.CrossRefPubMedGoogle Scholar
  21. 21.
    Yang SK, Kim H, Hong M, et al. Association of CARD8 with inflammatory bowel disease in Koreans. J Hum Genet. 2011;56:217–223.CrossRefPubMedGoogle Scholar
  22. 22.
    Carter JD, Valeriano J, Vasey FB. Crohn disease worsened by anakinra administration. J Clin Rheumatol. 2003;9:276–277.CrossRefPubMedGoogle Scholar
  23. 23.
    Pena Rossi C, Hanauer SB, Tomasevic R, Hunter JO, Shafran I, Graffner H. Interferon beta-1a for the maintenance of remission in patients with Crohn’s disease: results of a phase II dose-finding study. BMC Gastroenterol. 2009;9:22.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Lazaros-Dimitrios Lazaridis
    • 1
  • Aikaterini Pistiki
    • 2
  • Evangelos J. Giamarellos-Bourboulis
    • 2
  • Marianna Georgitsi
    • 2
  • Georgia Damoraki
    • 2
  • Dimitrios Polymeros
    • 1
  • George D. Dimitriadis
    • 1
  • Konstantinos Triantafyllou
    • 1
  1. 1.Hepatogastroenterology Unit, 2nd Department of Internal Medicine – Propaedeutic, Research Institute and Diabetes Center, Medical School, Attikon University General HospitalNational and Kapodistrian UniversityAthensGreece
  2. 2.4th Department of Internal Medicine, Medical School, Attikon University General HospitalNational and Kapodistrian UniversityAthensGreece

Personalised recommendations