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Erschienen in: Virchows Archiv 6/2009

01.06.2009 | Original Article

The antimicrobial peptide HBD-2 and the Toll-like receptors-2 and -4 are induced in synovial membranes in case of septic arthritis

verfasst von: D. Varoga, E. Klostermeier, F. Paulsen, C. Wruck, S. Lippross, L. O. Brandenburg, M. Tohidnezhad, A. Seekamp, B. Tillmann, T. Pufe

Erschienen in: Virchows Archiv | Ausgabe 6/2009

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Abstract

Septic arthritis is frequently observed especially in immune-compromised or chronically diseased patients and leads to functional impairment due to tissue destruction. Recently, production of antimicrobial peptides (AMP) was observed in articular cartilage after exposure to bacteria. This report examines the role of synoviocyte-derived AMPs in innate defense mechanisms of articular joints. Samples of healthy, low-grade synovialitis and septic synovial membranes were assessed for the expression of human β-defensin-2 (HBD-2) and Toll-like receptor-2 and -4 (TLR) by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA). A stable synoviocyte line (K4IM) was used for in vitro experiments and assayed for endogenous HBD-2 and TLR production after exposure to inflammatory cytokines or bacterial supernatants by reverse transcription polymerase chain reaction (RT-PCR), real-time RT-PCR, Western blot, ELISA, and dual luciferase assay. Healthy human synovial membranes and cultured synoviocytes are able to produce HBD-2 and TLR-1–5 at basal expression levels. Samples of bacteria-colonized synovial membranes produce higher levels of HBD-2 when compared with samples of healthy tissues. K4IM synoviocytes exposed to Staphylococcus aureus, Pseudomonas aeruginosa, or proinflammatory cytokines demonstrated a clear HBD-2 transcription and protein induction. TLR-2 and -4 are known to have a critical role in the recognition of gram-positive and gram-negative bacteria in epithelia and are induced in mesenchymal synoviocytes after bacterial exposure on transcription and on protein level. This report demonstrates an unappreciated role of synovial membranes: samples of septic synovial membranes and cultured synoviocytes exposed to bacteria produce increased amounts of the AMP HBD-2 and the bacteria recognition receptors TLR-2 and -4. The induction of anti-inflammatory pathways in infected synoviocytes suggests involvement in intra-articular defense mechanisms.
Literatur
2.
Zurück zum Zitat Ross JJ (2005) Septic arthritis. Infect Dis Clin North Am 4:799–817CrossRef Ross JJ (2005) Septic arthritis. Infect Dis Clin North Am 4:799–817CrossRef
3.
Zurück zum Zitat Jasin HE (1983) Bacterial lipopolysaccharides induce in-vitro degradation of cartilage matrix through chondrocyte activation. J Clin Invest 72:2014–2019PubMedCrossRef Jasin HE (1983) Bacterial lipopolysaccharides induce in-vitro degradation of cartilage matrix through chondrocyte activation. J Clin Invest 72:2014–2019PubMedCrossRef
4.
Zurück zum Zitat Deng GM, Verdrengh M, Liu ZQ et al (2000) The major role of macrophages and their product tumor necrosis factor alpha in the induction of arthritis triggered by bacterial DNA containing CpG motifs. Arthritis Rheum 43:2283–2289PubMedCrossRef Deng GM, Verdrengh M, Liu ZQ et al (2000) The major role of macrophages and their product tumor necrosis factor alpha in the induction of arthritis triggered by bacterial DNA containing CpG motifs. Arthritis Rheum 43:2283–2289PubMedCrossRef
5.
Zurück zum Zitat Hsieh YS, Yang SF, Lue KH et al (2006) Clinical correlation with the PA/plasmin system in septic arthritis of the knee. Clin Orthop Relat Res 447:172–178PubMedCrossRef Hsieh YS, Yang SF, Lue KH et al (2006) Clinical correlation with the PA/plasmin system in septic arthritis of the knee. Clin Orthop Relat Res 447:172–178PubMedCrossRef
6.
Zurück zum Zitat Castor CW (1960) The microscopic structure of normal human synovial tissue. Arthritis Rheum 3:140–151PubMedCrossRef Castor CW (1960) The microscopic structure of normal human synovial tissue. Arthritis Rheum 3:140–151PubMedCrossRef
7.
Zurück zum Zitat Barland P, Novikoff AB, Hamerman D (1962) Electron microscopy of the human synovial membrane. J Cell Biol 14:207–220PubMedCrossRef Barland P, Novikoff AB, Hamerman D (1962) Electron microscopy of the human synovial membrane. J Cell Biol 14:207–220PubMedCrossRef
8.
Zurück zum Zitat Wilkinson LS, Pitsillides AA, Worrall JG et al (1992) Light microscopic characterization of the fibroblast-like synovial intimal cell (synoviocyte). Arthritis Rheum 35:1179–1184PubMedCrossRef Wilkinson LS, Pitsillides AA, Worrall JG et al (1992) Light microscopic characterization of the fibroblast-like synovial intimal cell (synoviocyte). Arthritis Rheum 35:1179–1184PubMedCrossRef
9.
Zurück zum Zitat Stevens CR, Mapp PI, Revell PA (1990) A monoclonal antibody (Mab 67) marks type B synoviocytes. Rheumatol Int 10:103–106PubMedCrossRef Stevens CR, Mapp PI, Revell PA (1990) A monoclonal antibody (Mab 67) marks type B synoviocytes. Rheumatol Int 10:103–106PubMedCrossRef
10.
11.
Zurück zum Zitat Ganz T (2003) Defensins: antimicrobial peptides of innate immunity. Nat Rev Immunol 3:710–720PubMedCrossRef Ganz T (2003) Defensins: antimicrobial peptides of innate immunity. Nat Rev Immunol 3:710–720PubMedCrossRef
12.
Zurück zum Zitat Harder J, Bartels J, Christophers E et al (1997) A peptide antibiotic from human skin. Nature 387:861PubMedCrossRef Harder J, Bartels J, Christophers E et al (1997) A peptide antibiotic from human skin. Nature 387:861PubMedCrossRef
13.
Zurück zum Zitat Valore EV, Park CH, Quale AJ et al (1998) Human β-defensin-1: an antimicrobial peptide of urogenital tissue. J Clin Invest 101:1633–1642PubMedCrossRef Valore EV, Park CH, Quale AJ et al (1998) Human β-defensin-1: an antimicrobial peptide of urogenital tissue. J Clin Invest 101:1633–1642PubMedCrossRef
14.
Zurück zum Zitat Harder J, Bartels J, Christophers E et al (2001) Isolation and characterization of human β-defensin-3, a novel human inducible peptide antibiotic. J Biol Chem 276:5707–5713PubMedCrossRef Harder J, Bartels J, Christophers E et al (2001) Isolation and characterization of human β-defensin-3, a novel human inducible peptide antibiotic. J Biol Chem 276:5707–5713PubMedCrossRef
15.
Zurück zum Zitat Garcia JR, Krause A, Schulz S et al (2001) Human beta-defensin 4: a novel inducible peptide with a specific salt-sensitive spectrum of antimicrobial activity. FASEB J 15:1819–1821PubMed Garcia JR, Krause A, Schulz S et al (2001) Human beta-defensin 4: a novel inducible peptide with a specific salt-sensitive spectrum of antimicrobial activity. FASEB J 15:1819–1821PubMed
16.
Zurück zum Zitat Garcia JR, Jaumann F, Schulz S et al (2001) Identification of a novel, multifunctional beta-defensin (human beta-defensin 3) with specific antimicrobial activity. Its interaction with plasma membranes of Xenopus oocytes and the induction of macrophage chemoattraction. Cell Tissue Res 306:257–264PubMedCrossRef Garcia JR, Jaumann F, Schulz S et al (2001) Identification of a novel, multifunctional beta-defensin (human beta-defensin 3) with specific antimicrobial activity. Its interaction with plasma membranes of Xenopus oocytes and the induction of macrophage chemoattraction. Cell Tissue Res 306:257–264PubMedCrossRef
17.
Zurück zum Zitat Salzman NH, Ghosh D, Huttner KM et al (2003) Protection against enteric salmonellosis in transgenic mice expressing a human intestinal defensin. Nature 422:522–526PubMedCrossRef Salzman NH, Ghosh D, Huttner KM et al (2003) Protection against enteric salmonellosis in transgenic mice expressing a human intestinal defensin. Nature 422:522–526PubMedCrossRef
18.
Zurück zum Zitat Nizet V, Ohtake T, Lauth X et al (2001) Innate antimicrobial peptide protects the skin from invasive bacterial infection. Nature 414:454–457PubMedCrossRef Nizet V, Ohtake T, Lauth X et al (2001) Innate antimicrobial peptide protects the skin from invasive bacterial infection. Nature 414:454–457PubMedCrossRef
19.
Zurück zum Zitat Muzio M, Polentarutti N, Bosisio D et al (2000) Toll-like receptors: a growing family of immune receptors that are differentially expressed and regulated by different leukocytes. J Leukoc Biol 67:450–455PubMed Muzio M, Polentarutti N, Bosisio D et al (2000) Toll-like receptors: a growing family of immune receptors that are differentially expressed and regulated by different leukocytes. J Leukoc Biol 67:450–455PubMed
20.
Zurück zum Zitat Mushegian A, Medzhitov R (2001) Evolutionary perspective on innate immune recognition. J Cell Biol 155:705–711PubMedCrossRef Mushegian A, Medzhitov R (2001) Evolutionary perspective on innate immune recognition. J Cell Biol 155:705–711PubMedCrossRef
21.
Zurück zum Zitat Akira S, Takeda K, Kaisho T (2001) Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2:675–678PubMedCrossRef Akira S, Takeda K, Kaisho T (2001) Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2:675–678PubMedCrossRef
22.
Zurück zum Zitat Cook DN, Pisetsky DS, Schwartz DA (2004) Toll-like receptors in the pathogenesis of human disease. Nat Immunol 5:975–979PubMedCrossRef Cook DN, Pisetsky DS, Schwartz DA (2004) Toll-like receptors in the pathogenesis of human disease. Nat Immunol 5:975–979PubMedCrossRef
23.
24.
Zurück zum Zitat Suzuki M, Hisamatsu T, Podolsky K (2003) Y interferon augments intracellular pathway for LPS recognition in human intestinal epithelial cells through coordinated up-regulation of LPS uptake and expression of the intracellular TLR-4-MD-2 complex. Infect Immun 71:3503–3511PubMedCrossRef Suzuki M, Hisamatsu T, Podolsky K (2003) Y interferon augments intracellular pathway for LPS recognition in human intestinal epithelial cells through coordinated up-regulation of LPS uptake and expression of the intracellular TLR-4-MD-2 complex. Infect Immun 71:3503–3511PubMedCrossRef
25.
Zurück zum Zitat Paulsen F, Pufe T, Petersen W et al (2001) Expression of natural peptide antibiotics in human articular cartilage and synovial membrane. Clin Diagn Lab Immunol 8:1021–1023PubMed Paulsen F, Pufe T, Petersen W et al (2001) Expression of natural peptide antibiotics in human articular cartilage and synovial membrane. Clin Diagn Lab Immunol 8:1021–1023PubMed
26.
Zurück zum Zitat Paulsen F, Pufe T, Conradi L et al (2002) Antimicrobial peptides are expressed and produced in healthy and inflamed human synovial membranes. J Pathol 198:369–377PubMedCrossRef Paulsen F, Pufe T, Conradi L et al (2002) Antimicrobial peptides are expressed and produced in healthy and inflamed human synovial membranes. J Pathol 198:369–377PubMedCrossRef
27.
Zurück zum Zitat Haas C, Aicher WK, Dinkel A et al (1997) Characterization of SV40T antigen immortalized human synovial fibroblasts: maintained expression patterns of EGR-1, HLA-DR and some surface receptors. Rheumatol Int 16:241–247PubMedCrossRef Haas C, Aicher WK, Dinkel A et al (1997) Characterization of SV40T antigen immortalized human synovial fibroblasts: maintained expression patterns of EGR-1, HLA-DR and some surface receptors. Rheumatol Int 16:241–247PubMedCrossRef
28.
Zurück zum Zitat Hess S, Rheinheimer C, Tidow F et al (2001) The reprogrammed host: Chlamydia trachomatis-induced up-regulation of glycoprotein 130 cytokines, transcription factors, and antiapoptotic genes. Arthritis Rheum 44:2392–2401PubMedCrossRef Hess S, Rheinheimer C, Tidow F et al (2001) The reprogrammed host: Chlamydia trachomatis-induced up-regulation of glycoprotein 130 cytokines, transcription factors, and antiapoptotic genes. Arthritis Rheum 44:2392–2401PubMedCrossRef
29.
Zurück zum Zitat Ralph JA, McEvoy AN, Kane D et al (2005) Modulation of orphan nuclear receptor NURR1 expression by methotrexate in human inflammatory joint disease involves adenosine A2A receptor-mediated responses. J Immunol 175:555–565PubMed Ralph JA, McEvoy AN, Kane D et al (2005) Modulation of orphan nuclear receptor NURR1 expression by methotrexate in human inflammatory joint disease involves adenosine A2A receptor-mediated responses. J Immunol 175:555–565PubMed
30.
Zurück zum Zitat Gläser R, Harder J, Lange H et al (2005) Antimicrobial psoriasin (S100A7) protects human skin from Escherichia coli infection. Nat Immunol 1:57–64CrossRef Gläser R, Harder J, Lange H et al (2005) Antimicrobial psoriasin (S100A7) protects human skin from Escherichia coli infection. Nat Immunol 1:57–64CrossRef
31.
Zurück zum Zitat Varoga D, Pufe T, Harder J et al (2005) Human β-defensin-3 mediates tissue remodelling processes in articular cartilage by increasing metalloproteinases and reducing their endogenous inhibitors. Arthritis Rheum 52:1736–1745PubMedCrossRef Varoga D, Pufe T, Harder J et al (2005) Human β-defensin-3 mediates tissue remodelling processes in articular cartilage by increasing metalloproteinases and reducing their endogenous inhibitors. Arthritis Rheum 52:1736–1745PubMedCrossRef
32.
Zurück zum Zitat Varoga D, Paulsen FP, Kohrs S et al (2006) Expression and regulation of human beta-defensin-2 in osteoarthritis. J Pathol 209:166–173PubMedCrossRef Varoga D, Paulsen FP, Kohrs S et al (2006) Expression and regulation of human beta-defensin-2 in osteoarthritis. J Pathol 209:166–173PubMedCrossRef
33.
Zurück zum Zitat Pufe T, Petersen W, Tillmann B et al (2001) The angiogenic peptide vascular endothelial growth factor is expressed in foetal and ruptured tendons. Virchows Arch 439:579–585PubMedCrossRef Pufe T, Petersen W, Tillmann B et al (2001) The angiogenic peptide vascular endothelial growth factor is expressed in foetal and ruptured tendons. Virchows Arch 439:579–585PubMedCrossRef
34.
Zurück zum Zitat Harder J, Meyer-Hoffert U, Teran LM et al (2000) Mucoid Pseudomonas aeruginosa, TNF-alpha, and IL-1-beta, but not IL-6, induce human beta-defensin-2 in respiratory epithelia. Am J Respir Cell Mol Biol 22:714–721PubMed Harder J, Meyer-Hoffert U, Teran LM et al (2000) Mucoid Pseudomonas aeruginosa, TNF-alpha, and IL-1-beta, but not IL-6, induce human beta-defensin-2 in respiratory epithelia. Am J Respir Cell Mol Biol 22:714–721PubMed
35.
Zurück zum Zitat Liu L, Roberts AA, Ganz T (2003) By IL-1 signaling, monocyte-derived cells dramatically enhance the epidermal antimicrobial response to lipopolysaccharide. J Immunol 170:575–580PubMed Liu L, Roberts AA, Ganz T (2003) By IL-1 signaling, monocyte-derived cells dramatically enhance the epidermal antimicrobial response to lipopolysaccharide. J Immunol 170:575–580PubMed
36.
Zurück zum Zitat Bals R, Wang X, Wu Z et al (1998) Human beta-defensin 2 is a salt-sensitive peptide antibiotic expressed in human lung. J Clin Invest 102:874–880PubMedCrossRef Bals R, Wang X, Wu Z et al (1998) Human beta-defensin 2 is a salt-sensitive peptide antibiotic expressed in human lung. J Clin Invest 102:874–880PubMedCrossRef
37.
Zurück zum Zitat Becker MN, Diamond G, Verghese MW et al (2000) CD-14-dependent lipopolysaccharide-induced beta-defensin-2 expression in human tracheobronchial epithelium. J Biol Chem 275:29731–29736PubMedCrossRef Becker MN, Diamond G, Verghese MW et al (2000) CD-14-dependent lipopolysaccharide-induced beta-defensin-2 expression in human tracheobronchial epithelium. J Biol Chem 275:29731–29736PubMedCrossRef
38.
Zurück zum Zitat O’Neil DA, Porter EM, Elewaut D et al (1999) Expression and regulation of the human beta-defen-sins hBD-1 and HBD-2 in intestinal epithelium. J Immunol 163:6718–6724PubMed O’Neil DA, Porter EM, Elewaut D et al (1999) Expression and regulation of the human beta-defen-sins hBD-1 and HBD-2 in intestinal epithelium. J Immunol 163:6718–6724PubMed
39.
Zurück zum Zitat Varoga D, Pufe T, Harder J et al (2004) Production of endogenous antibiotics in articular cartilage. Arthritis Rheum 50:3526–3534PubMedCrossRef Varoga D, Pufe T, Harder J et al (2004) Production of endogenous antibiotics in articular cartilage. Arthritis Rheum 50:3526–3534PubMedCrossRef
40.
Zurück zum Zitat Yang D, Chertov O, Bykovskaia SN et al (1999) Beta-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science 286:525–528PubMedCrossRef Yang D, Chertov O, Bykovskaia SN et al (1999) Beta-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science 286:525–528PubMedCrossRef
41.
Zurück zum Zitat Punzi L, Peuravuori H, Jokilammi-Siltanen A et al (2000) Bactericidal/permeability increasing protein and proinflammatory cytokines in synovial fluid of psoriatic arthritis. Clin Exp Rheumatol 18:613–615PubMed Punzi L, Peuravuori H, Jokilammi-Siltanen A et al (2000) Bactericidal/permeability increasing protein and proinflammatory cytokines in synovial fluid of psoriatic arthritis. Clin Exp Rheumatol 18:613–615PubMed
42.
Zurück zum Zitat Bokarewa MI, Jin T, Tarkowski A (2003) Intraarticular release and accumulation of defensins and bactericidal/permeability-increasing protein in patients with rheumatoid arthritis. J Rheumatol 30:1719–1724PubMed Bokarewa MI, Jin T, Tarkowski A (2003) Intraarticular release and accumulation of defensins and bactericidal/permeability-increasing protein in patients with rheumatoid arthritis. J Rheumatol 30:1719–1724PubMed
Metadaten
Titel
The antimicrobial peptide HBD-2 and the Toll-like receptors-2 and -4 are induced in synovial membranes in case of septic arthritis
verfasst von
D. Varoga
E. Klostermeier
F. Paulsen
C. Wruck
S. Lippross
L. O. Brandenburg
M. Tohidnezhad
A. Seekamp
B. Tillmann
T. Pufe
Publikationsdatum
01.06.2009
Verlag
Springer-Verlag
Erschienen in
Virchows Archiv / Ausgabe 6/2009
Print ISSN: 0945-6317
Elektronische ISSN: 1432-2307
DOI
https://doi.org/10.1007/s00428-009-0780-4

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