BACKGROUND: Ankylosing enthesopathy (ANKENT) is an animal model of human ankylosing spondylitis. ANKENT is an inflammatory disease affecting the ankle and tarsal joints of the hind limbs in susceptible mouse strains. In the disease, the participation of intestinal microbiota components was suggested. Therefore, we attempted to increase the incidence of ANKENT by systemic administration of lipopolysaccharide (LPS), which is a component of bacterial cellular walls and stimulates inflammatory processes. METHODS: ANKENT occurrence, serum cytokine profiles, spleen cellular composition and in vitro cytokine response to LPS were analysed in LPS-treated and control LPS-untreated B10.BR male mice. RESULTS: Contrary to expectations, LPS treatment decreased the incidence of ANKENT in LPS-treated group compared to control LPS-untreated group. Flow cytometry analysis of splenocytes showed an increased percentage of macrophages, dendritic cells and neutrophils and a decreased percentage of B cells, T cells and T helper cells in LPS-treated males following LPS administration. In addition, LPS-treated males had significantly elevated IL-6 and IL-10 serum levels. At 20-22 weeks after the final LPS application, splenocytes from LPS-treated mice were more susceptible to in vitro LPS stimulation than those of the controls and produced significantly higher levels of TNFα and IL-6. CONCLUSIONS: Repeated systemic stimulation with microbial component lipopolysaccharide in early adulthood significantly reduced the incidence of ANKENT in B10.BR mice and this finding can support the "hygiene hypothesis". In LPS-treated mice, the innate immunity parameters and the level of anti-inflammatory IL-10 cytokine were significantly increased. Nevertheless, the immunological mechanism of the LPS protective effect remains unclear.

Laboratory of Diagnostics for Reproductive Medicine Institute of Biotechnology AS CR v v i Videnska 1083 Prague 142 20 Czech Republic

Zobrazit více v PubMed

Brewerton DA, Hart FD, Nicholls A, Caffrey M, James DC, Sturrock RD. Ankylosing spondylitis and HL-A 27. Lancet. 1973;1:904–907. PubMed

Schlosstein L, Terasaki PI, Bluestone R, Pearson CM. High association of an HL-A antigen, W27, with ankylosing spondylitis. N Engl J Med. 1973;288:704–706. PubMed

Breban M, Hacquard-Bouder C, Falgarone G. Animal models of HLA-B27-associated diseases. Curr Mol Med. 2004;4:31–40. PubMed

Khare SD, Luthra HS, David CS. Spontaneous inflammatory arthritis in HLA-B27 transgenic mice lacking beta 2-microglobulin: a model of human spondyloarthropathies. J Exp Med. 1995;182:1153–1158. PubMed PMC

Nordling C, Karlsson-Parra A, Jansson L, Holmdahl R, Klareskog L. Characterization of a spontaneously occurring arthritis in male DBA/1 mice. Arthritis Rheum. 1992;35:717–722. PubMed

Taurog JD. Animal models of spondyloarthritis. Adv Exp Med Biol. 2009;649:245–254. PubMed

D'Agostino MA, Said-Nahal R, Hacquard-Bouder C, Brasseur JL, Dougados M, Breban M. Assessment of peripheral enthesitis in the spondylarthropathies by ultrasonography combined with power Doppler: a cross-sectional study. Arthritis Rheum. 2003;48:523–533. PubMed

Granfors K, Marker-Hermann E, de Keyser F, Khan MA, Veys EM, Yu DT. The cutting edge of spondylarthropathy research in the millennium. Arthritis Rheum. 2002;46:606–613. PubMed

Eulderink F, Ivanyi P, Weinreich S. Histopathology of murine ankylosing enthesopathy. Pathol Res Pract. 1998;194:797–803. PubMed

Capkova J, Ivanyi P. H-2 influence on ankylosing enthesopathy of the ankle (ANKENT) Folia Biol (Praha) 1992;38:258–262. PubMed

Weinreich S, Eulderink F, Capkova J, Pla M, Gaede K, Heesemann J, van Alphen L, Zurcher C, Hoebe-Hewryk B, Kievits F. et al.HLA-B27 as a relative risk factor in ankylosing enthesopathy in transgenic mice. Hum Immunol. 1995;42:103–115. PubMed

Capkova J, Ivanyi P, Rehakova Z. Sexual dimorphism, but not testosterone itself, is responsible for ankylosing enthesitis of the ankle in B10.BR (H-2k) male mice. Ann Rheum Dis. 2006;65:130–132. PubMed PMC

Rehakova Z, Capkova J, Stepankova R, Sinkora J, Louzecka A, Ivanyi P, Weinreich S. Germ-free mice do not develop ankylosing enthesopathy, a spontaneous joint disease. Hum Immunol. 2000;61:555–558. PubMed

Sinkorova Z, Capkova J, Niederlova J, Stepankova R, Sinkora J. Commensal intestinal bacterial strains trigger ankylosing enthesopathy of the ankle in inbred B10.BR (H-2(k)) male mice. Hum Immunol. 2008;69:845–850. PubMed

Tlaskalova-Hogenova H, Stepankova R, Hudcovic T, Tuckova L, Cukrowska B, Lodinova-Zadnikova R, Kozakova H, Rossmann P, Bartova J, Sokol D. et al.Commensal bacteria (normal microflora), mucosal immunity and chronic inflammatory and autoimmune diseases. Immunol Lett. 2004;93:97–108. PubMed

Munford RS. Sensing gram-negative bacterial lipopolysaccharides: a human disease determinant? Infect Immun. 2008;76:454–465. PubMed PMC

Mishima S, Xu D, Lu Q, Deitch EA. The relationships among nitric oxide production, bacterial translocation, and intestinal injury after endotoxin challenge in vivo. J Trauma. 1998;44:175–182. PubMed

Westphal O, Luderitz O, Bister F. Uber die Extraktion von Bakterien mit Phenol/Wasser. Z Naturforsch. 1952;7:148–155.

Aird WC. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood. 2003;101:3765–3777. PubMed

Guha M, Mackman N. LPS induction of gene expression in human monocytes. Cell Signal. 2001;13:85–94. PubMed

Holmdahl R, Jansson L, Andersson M, Jonsson R. Genetic, hormonal and behavioural influence on spontaneously developing arthritis in normal mice. Clin Exp Immunol. 1992;88:467–472. PubMed PMC

Weinreich S, Capkova J, Hoebe-Hewryk B, Boog C, Ivanyi P. Grouped caging predisposes male mice to ankylosing enthesopathy. Ann Rheum Dis. 1996;55:645–647. PubMed PMC

Hacquard-Bouder C, Ittah M, Breban M. Animal models of HLA-B27-associated diseases: new outcomes. Joint Bone Spine. 2006;73:132–138. PubMed

Milia AF, Ibba-Manneschi L, Manetti M, Benelli G, Messerini L, Matucci-Cerinic M. HLA-B27 transgenic rat: an animal model mimicking gut and joint involvement in human spondyloarthritides. Ann N Y Acad Sci. 2009;1173:570–574. PubMed

Onderdonk AB, Richardson JA, Hammer RE, Taurog JD. Correlation of cecal microflora of HLA-B27 transgenic rats with inflammatory bowel disease. Infect Immun. 1998;66:6022–6023. PubMed PMC

Rath HC, Herfarth HH, Ikeda JS, Grenther WB, Hamm TE, Balish E, Taurog JD, Hammer RE, Wilson KH, Sartor RB. Normal luminal bacteria, especially Bacteroides species, mediate chronic colitis, gastritis, and arthritis in HLA-B27/human beta2 microglobulin transgenic rats. J Clin Invest. 1996;98:945–953. PubMed PMC

Taurog JD, Richardson JA, Croft JT, Simmons WA, Zhou M, Fernandez-Sueiro JL, Balish E, Hammer RE. The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J Exp Med. 1994;180:2359–2364. PubMed PMC

Ciccia F, Bombardieri M, Principato A, Giardina A, Tripodo C, Porcasi R, Peralta S, Franco V, Giardina E, Craxi A. et al.Overexpression of interleukin-23, but not interleukin-17, as an immunologic signature of subclinical intestinal inflammation in ankylosing spondylitis. Arthritis Rheum. 2009;60:955–965. PubMed

de Vlam K, Mielants H, Cuvelier C, De Keyser F, Veys EM, De Vos M. Spondyloarthropathy is underestimated in inflammatory bowel disease: prevalence and HLA association. J Rheumatol. 2000;27:2860–2865. PubMed

Faustini F, Zoli A, Ferraccioli GF. Immunologic and genetic links between spondylarthropathies and inflammatory bowel diseases. Eur Rev Med Pharmacol Sci. 2009;13(Suppl 1):1–9. PubMed

Jacques P, Mielants H, Coppieters K, De Vos M, Elewaut D. The intimate relationship between gut and joint in spondyloarthropathies. Curr Opin Rheumatol. 2007;19:353–357. PubMed

Palm O, Moum B, Ongre A, Gran JT. Prevalence of ankylosing spondylitis and other spondyloarthropathies among patients with inflammatory bowel disease: a population study (the IBSEN study) J Rheumatol. 2002;29:511–515. PubMed

Rodriguez-Reyna TS, Martinez-Reyes C, Yamamoto-Furusho JK. Rheumatic manifestations of inflammatory bowel disease. World J Gastroenterol. 2009;15:5517–5524. PubMed PMC

Biswas A, Wilmanski J, Forsman H, Hrncir T, Hao L, Tlaskalova-Hogenova H, Kobayashi KS. Negative regulation of Toll-like receptor signaling plays an essential role in homeostasis of the intestine. Eur J Immunol. 2011;41:182–194. PubMed PMC

Barsig J, Kusters S, Vogt K, Volk HD, Tiegs G, Wendel A. Lipopolysaccharide-induced interleukin-10 in mice: role of endogenous tumor necrosis factor-alpha. Eur J Immunol. 1995;25:2888–2893. PubMed

Zhang WJ, Wei H, Hagen T, Frei B. Alpha-lipoic acid attenuates LPS-induced inflammatory responses by activating the phosphoinositide 3-kinase/Akt signaling pathway. Proc Natl Acad Sci U S A. 2007;104:4077–4082. PubMed PMC

Old LJ. Tumor necrosis factor (TNF) Science. 1985;230:630–632. PubMed

Oldfield V, Plosker GL. Golimumab: in the treatment of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. BioDrugs. 2009;23:125–135. PubMed

Sieper J. Developments in the scientific and clinical understanding of the spondyloarthritides. Arthritis Res Ther. 2009;11:208. PubMed PMC