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Rheumatology International

, Volume 34, Issue 2, pp 213–220 | Cite as

Changes in toll-like receptor (TLR)4–NFκB–IL1β signaling in male gout patients might be involved in the pathogenesis of primary gouty arthritis

  • Yu-Feng Qing
  • Quan-Bo Zhang
  • Jing-Guo ZhouEmail author
  • Li Jiang
Original Article

Abstract

We undertook this study to determine whether the altered toll-like receptor (TLR)4-nuclear factor κB (NFκB)-interleukin1β (IL1β) signaling in peripheral blood of gout patients could provide insights into the pathogenesis of primary gouty arthritis (GA). TLR4 mRNA, TLR4 and NFκBp65 proteins expression and IL1β production were measured in 52 acute GA (AGA) and 34 non-acute GA (NAGA) male patients and 78 male healthy subjects (HC). NFκBp65 transcriptional activity and IL1β production were measured after TLR4 inhibition with anti-TLR4 antibody in peripheral whole blood from 13 AGA patients. The TLR4, NFκBp65 and IL1β expression was significantly increased in the AGA group than those in the NAGA or HC group (P < 0.05, respectively), also the levels were higher in the NAGA group comparing with those in the HC group (P < 0.05, respectively). Furthermore, moderate positive correlations were observed between concentration of uric acid and the TLR4 mRNA level, serum IL1β production (r = 0.649, 0.616), and strong positive correlation was observed between TLR4 mRNA level and serum IL1β (r = 0.848) in 52 AGA patients. On the other hand, NFκBp65 level and IL1β production were dramatically reduced after TLR4 blockade with anti-TLR4 antibody in peripheral blood from the AGA patients (P < 0.05, respectively). TLR4–NFκB–IL1β signaling might play a crucial role in the development of acute inflammation in primary gout patients.

Keywords

Gouty arthritis Primary TLR4 Signaling 

Notes

Acknowledgments

This work was partly supported by Natural Science Foundation of China (81272047) and Key Program, Science and Technology Bureau of Sichuan (2012SZ0171).

Conflict of interest

All the authors declare that they have no conflicts of interest.

References

  1. 1.
    Richette P, Bardin T (2010) Gout. Lancet 375:318–328PubMedCrossRefGoogle Scholar
  2. 2.
    Baker JF, Schumacher HR (2010) Update on gout and hyperuricemia. Int J Clin Pract 64:371–377PubMedCrossRefGoogle Scholar
  3. 3.
    Weaver AL (2008) Epidemiology of gout. Clevel Clin J Med 75:S9–12CrossRefGoogle Scholar
  4. 4.
    Miao Z, Li C, Chen Y et al (2008) Dietary and lifestyle changes associated with high prevalence of hyperuricemia and gout in the Shandong coastal cities of Eastern China. J Rheumatol 35:1859–1864PubMedGoogle Scholar
  5. 5.
    Annemans L, Spaepen E, Gaskin M et al (2008) Gout in the UK and Germany: prevalence, comorbidities and management in general practice 2000–2005. Ann Rheum Dis 67:960–966PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Taniguchi A, Kammatani N (2008) Control of renal uric acid excretion and gout. Curr Opin Rheumatol 20:192–197PubMedCrossRefGoogle Scholar
  7. 7.
    Shin Y, Evans JE, Rock KL (2003) Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425:516–521CrossRefGoogle Scholar
  8. 8.
    Ghaemi-Oskouie F, Shi Y (2011) The Role of Uric Acid as an Endogenous Danger Signal in Immunity and Inflammation. Curr Rheumatol Rep 13:160–166PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Martinon F, Mayor A, Tschopp J (2009) The inflammasomes: guardians of the body. Annu Rev Immunol 27:229–265PubMedCrossRefGoogle Scholar
  10. 10.
    Poltorak A, He X, Smirnova I (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282:2085–2088PubMedCrossRefGoogle Scholar
  11. 11.
    Hoshino K, Takeuchi O, Kawai T (1999) Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol 162:3749–3752PubMedGoogle Scholar
  12. 12.
    Ohashi K, Burkart V, Flohe S et al (2000) Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J Immunol 164:558–561PubMedGoogle Scholar
  13. 13.
    Termeer C, Benedix F, Sleeman J et al (2002) Oligosaccharides of hyaluronan activate dendritic cells via toll-like receptor 4. J Exp Med 195:99–111PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Okamura Y, Watari M, Jerud ES et al (2001) The extra domain A of Wbronectin activates toll-like receptor 4. J Biol Chem 276:10229–10233PubMedCrossRefGoogle Scholar
  15. 15.
    Liu-Bryan R, Pritzker K, Firestein GS et al (2005) TLR2 signaling in chondrocytes derives calcium pyrophosphate dehydrate and monosodium urate crystal-induced nitric oxide generation. J Immunol 174:5016–5023PubMedGoogle Scholar
  16. 16.
    Liu-Bryan R, Scott P, Sydlaske A et al (2005) Innate immunity conferred by toll-like receptor 2 and 4 and myeloid differentiation factor 88 expression is pivotal to monosodium urate monohydrate crystal-induced inflammation. Arthritis Rheum 52:2936–2946PubMedCrossRefGoogle Scholar
  17. 17.
    Chen CJ, Shi Y, Hearn A et al (2006) MyD88-dependent IL-1 receptor signaling is essential for gouty inflammation stimulated by monosodium urate crystals. J Clin Invest 116:2262–2271PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Wallace SL, Robinson H, Masi AT et al (1977) Preliminary criteria for the classification of the acute arthritis of the acute arthritis of primary gout. Arthritis Rheum 20:895–900PubMedCrossRefGoogle Scholar
  19. 19.
    Qing YF, Zhou JG, Zhang QB et al (2013) Association of TLR4 Gene rs2149356 Polymorphism with Primary Gouty Arthritis in a Case-Control Study. PLoS One 8:e64845PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Qing YF, Zhou JG, Zhao MC et al (2012) Altered expression of TPP1 in fibroblast-like synovial cells might be involved in the pathogenesis of rheumatoid arthritis. Rheumatol Int 32:2503–2510PubMedCrossRefGoogle Scholar
  21. 21.
    Zhou JG, Qing YF, Yang QB et al (2011) Changes in the expression of telomere maintenance genes might play a role in the pathogenesis of systemic lupus erythematosus. Lupus 20:820–828PubMedCrossRefGoogle Scholar
  22. 22.
    Chang JH, Hampartzoumian T, Everett B et al (2007) Changes in Toll-like receptor (TLR)-2 and TLR4 expression and function but not polymorphisms are associated with acute anterior uveitis. Invest Ophthalmol Vis Sci 48:1711–1717PubMedCrossRefGoogle Scholar
  23. 23.
    de Graaf R, Kloppenburg G, Kitslaar PJ et al (2006) Human heat shock protein 60 stimulates vascular smooth muscle cell proliferation through Toll-like receptors 2 and 4. Microbes Infect 8:1859–1865PubMedCrossRefGoogle Scholar
  24. 24.
    Kusunoki N, Kitahara K, Kojima F et al (2010) Adiponectin Stimulates Prostaglandin E2 Production in Rheumatoid Arthritis Synovial Fibroblasts. Arthritis Rheum 62:1641–1649PubMedCrossRefGoogle Scholar
  25. 25.
    Scott P, Ma H, Viriyakosol S, et al. Engagement of CD14 mediates the inflammatory potential of monosodium urate crystals. J Immunol 177: 6370-6378Google Scholar
  26. 26.
    Martinon F, Pétrilli V, Mayor A et al (2006) Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440:237–241PubMedCrossRefGoogle Scholar
  27. 27.
    So A, de Smedt T, Revaz S et al (2007) A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res Ther 9:R28PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Terkeltaub R, Sundy JS, Schumacher HR et al (2009) The interleukin 1 inhibitor rilonacept in treatment of chronic gouty arthritis: results of a placebo-controlled, monosequence crossover, non-randomised, single-blind pilot study. Ann Rheum Dis 68:1613–1617PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Burns K, Martinon F, Tschopp J (2003) New insights into the mechanism of IL-1beta maturation. Curr Opin Immunol 15:26–30PubMedCrossRefGoogle Scholar
  30. 30.
    McCormack WJ, Parker AE, O’Neill LA (2009) Toll-like receptors and NOD-like receptors in rheumatic diseases. Arthritis Res Ther 11:243PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Goldbach-Mansky R, Dailey NJ, Canna SW et al (2006) Neonatal-onset multisystem inflammatory disease responsive to interleukin-1β inhibition. N Engl J Med 355:581–592PubMedCrossRefGoogle Scholar
  32. 32.
    Miao ZM, Zhao SH, Wang YG et al (2006) Epidemiological survey of hyperuricemia and gout in coastal areas of Shandong province. Chin J Endocrinol Metab 22:421–425Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Yu-Feng Qing
    • 1
  • Quan-Bo Zhang
    • 2
  • Jing-Guo Zhou
    • 1
    Email author
  • Li Jiang
    • 1
  1. 1.Institute of Rheumatology and Immunology, Department of Rheumatology and HematologyThe Affiliated Hospital of North Sichuan Medical CollegeNanchongChina
  2. 2.Department of GeriatricsThe Affiliated Hospital of North Sichuan Medical CollegeNanchongChina

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