Skip to main content
Top
Published in: Rheumatology International 10/2008

01-08-2008 | Original Article

High levels of Lymphotoxin-Beta (LT-Beta) gene expression in rheumatoid arthritis synovium: clinical and cytokine correlations

Authors: Killian P. O’Rourke, G. O’Donoghue, C. Adams, H. Mulcahy, C. Molloy, C. Silke, M. Molloy, F. Shanahan, F. O’Gara

Published in: Rheumatology International | Issue 10/2008

Login to get access

Abstract

Lymphotoxin-Beta (LT-Beta) is implicated in lymphoid follicle development, production of pro-inflammatory cytokines, and can enhance the proliferation of fibroblasts and synoviocytes. The objective of this study was to investigate LT-Beta and LT-BetaReceptor (LT-BetaR) gene expression in RA patient synovium and blood samples compared with control individuals, and correlate with LT-Alpha and TNF-Alpha gene expression and disease parameters. RT-PCR was used to investigate the gene expression of LT-Beta, LT-BetaR, TNF-Alpha and LT-Alpha in the blood and synovium of RA patients and a control group of individuals. LT-Beta gene expression was significantly higher in RA patient synovium compared to control synovium (P = 0.005). There was a significant positive correlation between LT-Beta and LT-Alpha gene expression in both the synovium (P = 0.001) and blood (P = 0.002) of RA patients. LT-Beta gene expression was significantly higher in RA patient synovial samples that were inflamed to a moderately severe degree compared to those inflamed to a minimal degree (P = 0.02). Analysis of clinical variables revealed a significant positive correlation between LT-BetaR gene expression in RA patient synovium and Pain VAS Score (P = 0.01) and also HAQ Score (P = 0.01). Increased LT-Beta gene expression occurs in RA synovium and correlates with the degree of inflammation. LT-Beta may play a role in RA disease pathogenesis by contributing to a more intense inflammatory reaction in the synovium.
Literature
1.
go back to reference Seldin MF, Amos CI, Ward R, Gregersen PK (1999) The genetics revolution and the assault on rheumatoid arthritis. Arthritis Rheum 42:1071–1079PubMedCrossRef Seldin MF, Amos CI, Ward R, Gregersen PK (1999) The genetics revolution and the assault on rheumatoid arthritis. Arthritis Rheum 42:1071–1079PubMedCrossRef
2.
go back to reference Feldmann M, Brennan FM, Maini RN (1996) Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 14:397–440PubMedCrossRef Feldmann M, Brennan FM, Maini RN (1996) Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 14:397–440PubMedCrossRef
3.
go back to reference Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KJ, Fleischmann RM, Fox RI et al (1999) A trial of Etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. NEJM 340:253–259PubMedCrossRef Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KJ, Fleischmann RM, Fox RI et al (1999) A trial of Etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. NEJM 340:253–259PubMedCrossRef
4.
go back to reference Browning JL, Ngam-ek A, Lawton P, DeMarinis J, Tizard R, Chow EP et al (1993) Lymphotoxin beta, a novel member of the TNF family that forms a heteromeric complex with lymphotoxin on the cell surface. Cell 26:847–856CrossRef Browning JL, Ngam-ek A, Lawton P, DeMarinis J, Tizard R, Chow EP et al (1993) Lymphotoxin beta, a novel member of the TNF family that forms a heteromeric complex with lymphotoxin on the cell surface. Cell 26:847–856CrossRef
5.
go back to reference Lu G, Janjic BM, Janjic J, Whiteside TL, Storkus WJ, Vujanovic NL (2002) Innate direct anticancer effector function of human immature dendritic cells. II. Role of TNF, Lymphotoxin-[alpha]1[beta]2, fas ligand, and TNF-related apoptosis-inducing ligand. J Immunol 168:1831–1839PubMed Lu G, Janjic BM, Janjic J, Whiteside TL, Storkus WJ, Vujanovic NL (2002) Innate direct anticancer effector function of human immature dendritic cells. II. Role of TNF, Lymphotoxin-[alpha]1[beta]2, fas ligand, and TNF-related apoptosis-inducing ligand. J Immunol 168:1831–1839PubMed
6.
go back to reference Agyekum S, Church A, Sohail M, Krausz T, Van Noorden S, Polak J et al (2003) Expression of lymphotoxin-beta (LT-Beta) in chronic inflammatory conditions. J Pathol 199:115–21PubMedCrossRef Agyekum S, Church A, Sohail M, Krausz T, Van Noorden S, Polak J et al (2003) Expression of lymphotoxin-beta (LT-Beta) in chronic inflammatory conditions. J Pathol 199:115–21PubMedCrossRef
7.
go back to reference Shlopov BV, Gumanovskaya ML, Hasty KA (2000) Autocrine regulation of collagenase 3 (Matrix Metallo Proteinase 13) during osteoarthritis. Arthritis Rheum 43:195–205PubMedCrossRef Shlopov BV, Gumanovskaya ML, Hasty KA (2000) Autocrine regulation of collagenase 3 (Matrix Metallo Proteinase 13) during osteoarthritis. Arthritis Rheum 43:195–205PubMedCrossRef
8.
go back to reference Mackay F, Majeau GR, Hochman PS, Browning JL. (1996) Lymphotoxin beta receptor triggering induces activation of the nuclear factor kappaB transcription factor in some cell types. J Biol Chem 271:24934–8PubMedCrossRef Mackay F, Majeau GR, Hochman PS, Browning JL. (1996) Lymphotoxin beta receptor triggering induces activation of the nuclear factor kappaB transcription factor in some cell types. J Biol Chem 271:24934–8PubMedCrossRef
9.
go back to reference Mulcahy B, Waldron-Lynch F, McDermott MF, Adams C, Amos CI, Zhu DK, Ward RH, Clegg DO, Shanahan F, Molloy MG, O’Gara F (1996) Genetic variability in the tumor necrosis factor-lymphotoxin region influences susceptibility to rheumatoid arthritis. Am J Hum Genet 59(3):676–683PubMed Mulcahy B, Waldron-Lynch F, McDermott MF, Adams C, Amos CI, Zhu DK, Ward RH, Clegg DO, Shanahan F, Molloy MG, O’Gara F (1996) Genetic variability in the tumor necrosis factor-lymphotoxin region influences susceptibility to rheumatoid arthritis. Am J Hum Genet 59(3):676–683PubMed
10.
go back to reference Newton JL, Harney SM, Wordsworth BP, Brown MA (2004) A review of the MHC genetics of rheumatoid arthritis. Genes Immun 5:151–157PubMedCrossRef Newton JL, Harney SM, Wordsworth BP, Brown MA (2004) A review of the MHC genetics of rheumatoid arthritis. Genes Immun 5:151–157PubMedCrossRef
11.
go back to reference Mandik-Nayak L, Wipke BT, Shih FF, Unanue ER, Allen PM (2002) Despite ubiquitous autoantigen expression arthrogenic autoantibody response initiates in the local lymph node. PNAS 99:14368–14373PubMedCrossRef Mandik-Nayak L, Wipke BT, Shih FF, Unanue ER, Allen PM (2002) Despite ubiquitous autoantigen expression arthrogenic autoantibody response initiates in the local lymph node. PNAS 99:14368–14373PubMedCrossRef
12.
go back to reference Takemura S, Braun A, Crowson C, Kurtin PJ, Cofield RH, O`Fallon WM et al (2001) Lymphoid neogenesis in rheumatoid synovitis. J Immunol 167:1072–1080PubMed Takemura S, Braun A, Crowson C, Kurtin PJ, Cofield RH, O`Fallon WM et al (2001) Lymphoid neogenesis in rheumatoid synovitis. J Immunol 167:1072–1080PubMed
13.
go back to reference Rennert PD, James D, Mackay F, Browning JL, Hochman PS (1998) Lymph node genesis is induced by signaling through the lymphotoxin beta receptor. Immunity 9:71–79PubMedCrossRef Rennert PD, James D, Mackay F, Browning JL, Hochman PS (1998) Lymph node genesis is induced by signaling through the lymphotoxin beta receptor. Immunity 9:71–79PubMedCrossRef
14.
go back to reference Ramey DR, Raynaud JP, Fries JF (1992) The health assessment questionnaire 1992: status and review. Arthritis Care Res 5:119–129PubMedCrossRef Ramey DR, Raynaud JP, Fries JF (1992) The health assessment questionnaire 1992: status and review. Arthritis Care Res 5:119–129PubMedCrossRef
15.
go back to reference Anderson JJ, Chernoff MC (1993) Sensitivity to change of rheumatoid arthritis clinical trial outcome measures. J Rheumatol 20:535–537PubMed Anderson JJ, Chernoff MC (1993) Sensitivity to change of rheumatoid arthritis clinical trial outcome measures. J Rheumatol 20:535–537PubMed
16.
go back to reference Young CL, Adamson TC, Vaughan JH, Fox RI (1984) Immunohistologic characterization of synovial membrane lymphocytes in rheumatoid arthritis. Arthritis Rheum 27:32–39PubMedCrossRef Young CL, Adamson TC, Vaughan JH, Fox RI (1984) Immunohistologic characterization of synovial membrane lymphocytes in rheumatoid arthritis. Arthritis Rheum 27:32–39PubMedCrossRef
17.
go back to reference Krenn V, Souto-Carneiro MM, Kim HJ, Berek C, Starostik P, Konig A et al (2000) Hitopathology and molecular pathology of synovial B-lymphocytes in rheumatoid arthritis. Histol Histopathol 15:791–798PubMed Krenn V, Souto-Carneiro MM, Kim HJ, Berek C, Starostik P, Konig A et al (2000) Hitopathology and molecular pathology of synovial B-lymphocytes in rheumatoid arthritis. Histol Histopathol 15:791–798PubMed
18.
go back to reference Koizumi F, Matsuno H, Wakaki K, Ishii Y, Kurashige Y, Nakamura H (1999) Synovitis in rheumatoid arthritis: scoring of characteristic histopathological features. Pathol Int 49:298–304PubMedCrossRef Koizumi F, Matsuno H, Wakaki K, Ishii Y, Kurashige Y, Nakamura H (1999) Synovitis in rheumatoid arthritis: scoring of characteristic histopathological features. Pathol Int 49:298–304PubMedCrossRef
19.
go back to reference Raff T, Van der Giet M, Endemann D, Wiederholt T, Paul M (1997) Design and testing of beta-actin primers for RT-PCR that do not co-amplify pseudogenes. Biotechniques 23:456–460PubMed Raff T, Van der Giet M, Endemann D, Wiederholt T, Paul M (1997) Design and testing of beta-actin primers for RT-PCR that do not co-amplify pseudogenes. Biotechniques 23:456–460PubMed
20.
go back to reference Braun A, Takemura S, Vallejo AN, Goronzy JJ, Weyand CM (2004) Lymphotoxin beta-mediated stimulation of synoviocytes in rheumatoid arthritis. Arthritis Rheum 50:2140–2150PubMedCrossRef Braun A, Takemura S, Vallejo AN, Goronzy JJ, Weyand CM (2004) Lymphotoxin beta-mediated stimulation of synoviocytes in rheumatoid arthritis. Arthritis Rheum 50:2140–2150PubMedCrossRef
21.
go back to reference Ansel KM, Ngo VN, Hyman PL, Luther SA, Forster R, Sedgwick JD et al (2000) A Chemokine-driven positive feedback loop organizes lymphoid follicles. Nature 406:309–314PubMedCrossRef Ansel KM, Ngo VN, Hyman PL, Luther SA, Forster R, Sedgwick JD et al (2000) A Chemokine-driven positive feedback loop organizes lymphoid follicles. Nature 406:309–314PubMedCrossRef
22.
go back to reference Feldmann M, Andreakos E, Smith C, Bondeson J, Yoshimura S, Kiriakidis S et al (2002) Is NFkB a useful therapeutic target in rheumatoid arthritis. Ann Rheum Dis 61(Suppl 2):13–18 Feldmann M, Andreakos E, Smith C, Bondeson J, Yoshimura S, Kiriakidis S et al (2002) Is NFkB a useful therapeutic target in rheumatoid arthritis. Ann Rheum Dis 61(Suppl 2):13–18
23.
go back to reference Kuprash DV, Osipovich OA, Pokholok DK, Alimzhanov MB, Biragyn A, Turetskaya RL et al (1996) Functional analysis of the lymphotoxin-B promoter. J Immunol 156:2465–2472PubMed Kuprash DV, Osipovich OA, Pokholok DK, Alimzhanov MB, Biragyn A, Turetskaya RL et al (1996) Functional analysis of the lymphotoxin-B promoter. J Immunol 156:2465–2472PubMed
24.
go back to reference Voon DC, Subrata LS, Abraham LJ (2001) Regulation of lymphotoxin-beta by tumor necrosis factor, phorbol myristate acetate, and ionomycin in Jurkat T cells. J Interferon Cytokine Res 21:921–930PubMedCrossRef Voon DC, Subrata LS, Abraham LJ (2001) Regulation of lymphotoxin-beta by tumor necrosis factor, phorbol myristate acetate, and ionomycin in Jurkat T cells. J Interferon Cytokine Res 21:921–930PubMedCrossRef
25.
go back to reference Campbell IK, Piccoli DS, Roberts MJ, Muirden KD, Hamilton JA (1990) Effects of tumor necrosis factor alpha and beta on resorption of human articular cartilage and production of plasminogen activator by human articular chondrocytes. Arthritis Rheum 33:542–552PubMedCrossRef Campbell IK, Piccoli DS, Roberts MJ, Muirden KD, Hamilton JA (1990) Effects of tumor necrosis factor alpha and beta on resorption of human articular cartilage and production of plasminogen activator by human articular chondrocytes. Arthritis Rheum 33:542–552PubMedCrossRef
26.
go back to reference Thomson BM, Mundy GR, Chambers TJ (1987) Tumour necrosis factor alpha and beta induce osteoblastic cells to stimulate osteoclast bone resorption. J Immunol 138:775–779PubMed Thomson BM, Mundy GR, Chambers TJ (1987) Tumour necrosis factor alpha and beta induce osteoblastic cells to stimulate osteoclast bone resorption. J Immunol 138:775–779PubMed
27.
go back to reference Kowanko IC, Bates EJ, Ferrante A (1988) Tumour necrosis factor-beta modulates human neutrophil-mediated cartilage damage. Scand J Immunol 28:591–598PubMedCrossRef Kowanko IC, Bates EJ, Ferrante A (1988) Tumour necrosis factor-beta modulates human neutrophil-mediated cartilage damage. Scand J Immunol 28:591–598PubMedCrossRef
28.
go back to reference Kuprash DV, Boitchenko VE, Yarovinsky FO, Rice NR, Nordheim A, Ruhlmann A et al (2002) Cyclosporin A blocks the expression of lymphotoxin alpha, but not lymphotoxin beta in human peripheral blood mononuclear cells. Blood 100:1721–1727PubMed Kuprash DV, Boitchenko VE, Yarovinsky FO, Rice NR, Nordheim A, Ruhlmann A et al (2002) Cyclosporin A blocks the expression of lymphotoxin alpha, but not lymphotoxin beta in human peripheral blood mononuclear cells. Blood 100:1721–1727PubMed
29.
go back to reference Ettinger R (2000) The role of tumour necrosis factor and lymphotoxin in lymphoid organ development. Curr Top Microbiol Immunol 251:203–210PubMed Ettinger R (2000) The role of tumour necrosis factor and lymphotoxin in lymphoid organ development. Curr Top Microbiol Immunol 251:203–210PubMed
30.
go back to reference Smith C, Andreakos E, Crawley JB, Brennan FM, Feldmann M, Foxwell B (2001) NK-kB-inducing kinase is dispensible for activation of NF-kB in inflammatory settings but essential for lymphotoxin B receptor activation of NFkB in primary human fibroblasts. J Immunol 167:5895–5903PubMed Smith C, Andreakos E, Crawley JB, Brennan FM, Feldmann M, Foxwell B (2001) NK-kB-inducing kinase is dispensible for activation of NF-kB in inflammatory settings but essential for lymphotoxin B receptor activation of NFkB in primary human fibroblasts. J Immunol 167:5895–5903PubMed
31.
go back to reference Husson H, Lugli SM, Ghia P, Cardosso A, Roth A, Brohmi K et al (2000) Functional effects of TNF and lymphotoxin alpha1beta2 on FDC-like cells. Cell Immunol 203:134–143PubMedCrossRef Husson H, Lugli SM, Ghia P, Cardosso A, Roth A, Brohmi K et al (2000) Functional effects of TNF and lymphotoxin alpha1beta2 on FDC-like cells. Cell Immunol 203:134–143PubMedCrossRef
32.
go back to reference Arend WP, Dayer J-M (1990) Cytokine and cytokine inhibitors or antagonists in rheumatoid arthritis. Arthritis Rheum 33:305–315PubMedCrossRef Arend WP, Dayer J-M (1990) Cytokine and cytokine inhibitors or antagonists in rheumatoid arthritis. Arthritis Rheum 33:305–315PubMedCrossRef
33.
go back to reference Drouet C, Shahhov AN, Jongeneel CV (1991) Enhancers and transcription factors controlling inducibility of the tumor necrosis factor-alpha promoter in primary macrophages. J Immunol 147:1694–1700PubMed Drouet C, Shahhov AN, Jongeneel CV (1991) Enhancers and transcription factors controlling inducibility of the tumor necrosis factor-alpha promoter in primary macrophages. J Immunol 147:1694–1700PubMed
34.
go back to reference Kidd B (2004) What lessons can we learn from the study of pain pathways in rheumatic disease? J RCPE 34:66–67 Kidd B (2004) What lessons can we learn from the study of pain pathways in rheumatic disease? J RCPE 34:66–67
35.
go back to reference Wu Q, Saloman B, Chen M, Wang Y, Hoffman LM, Bluestone JA et al (2001) Reversal of spontaneous autoimmune insulitis in nonobese diabetic mice by soluble lymphotoxin receptor. J Exp Med 193:1327–1332PubMedCrossRef Wu Q, Saloman B, Chen M, Wang Y, Hoffman LM, Bluestone JA et al (2001) Reversal of spontaneous autoimmune insulitis in nonobese diabetic mice by soluble lymphotoxin receptor. J Exp Med 193:1327–1332PubMedCrossRef
36.
go back to reference Mackay F, Browning JL, Lawton P, Shah SA, Comiskey M, Bhan AK et al (1998) Both the lymphotoxin and tumour necrosis pathways are involved in experimental murine models of colitis. Gastroenterology 115:1464–1475PubMedCrossRef Mackay F, Browning JL, Lawton P, Shah SA, Comiskey M, Bhan AK et al (1998) Both the lymphotoxin and tumour necrosis pathways are involved in experimental murine models of colitis. Gastroenterology 115:1464–1475PubMedCrossRef
37.
go back to reference Tamada K, Tamura H, Flies D, Fu YX, Celis E, Pease LR et al (2002) Blockage of LIGHT / Ltbeta and CD 40 signalling induces allospecific T cell anergy, preventing graft-versus-host disease. J Clin Invest 109:549–557PubMed Tamada K, Tamura H, Flies D, Fu YX, Celis E, Pease LR et al (2002) Blockage of LIGHT / Ltbeta and CD 40 signalling induces allospecific T cell anergy, preventing graft-versus-host disease. J Clin Invest 109:549–557PubMed
Metadata
Title
High levels of Lymphotoxin-Beta (LT-Beta) gene expression in rheumatoid arthritis synovium: clinical and cytokine correlations
Authors
Killian P. O’Rourke
G. O’Donoghue
C. Adams
H. Mulcahy
C. Molloy
C. Silke
M. Molloy
F. Shanahan
F. O’Gara
Publication date
01-08-2008
Publisher
Springer-Verlag
Published in
Rheumatology International / Issue 10/2008
Print ISSN: 0172-8172
Electronic ISSN: 1437-160X
DOI
https://doi.org/10.1007/s00296-008-0574-z

Other articles of this Issue 10/2008

Rheumatology International 10/2008 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.