Lymphotoxin α stimulates proliferation and pro-inflammatory cytokine secretion of rheumatoid arthritis synovial fibroblasts

被引:35
作者
Calmon-Hamaty, Flavia [1 ]
Combe, Bernard [1 ,2 ,3 ]
Hahne, Michael [1 ,4 ]
Morel, Jacques [1 ,2 ,3 ]
机构
[1] CNRS UMR5535, Inst Genet Mol Montpellier, Montpellier, France
[2] Hop Lapeyronie, Montpellier, France
[3] Univ Montpellier I, Montpellier, France
[4] Univ Montpellier 2, Montpellier, France
关键词
Inflammatory cytokines; Lymphotoxin alpha; Proliferation; Rheumatoid arthritis; Synovial fibroblasts; TUMOR-NECROSIS-FACTOR; SIGNAL-TRANSDUCTION; LIGHT; APOPTOSIS; MEDIATOR; BETA; TNF; PATHOGENESIS; RECEPTORS; PATHWAYS;
D O I
10.1016/j.cyto.2010.10.010
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Objective: TNF alpha plays a crucial role in rheumatoid arthritis (RA) by stimulating fibroblast-like synoviocytes (FLS). Lymphotoxin alpha (LT alpha) is a pro-inflammatory cytokine with significant homology to INF alpha. We compared the effects of both cytokines on cultured RA FLS. Methods: Receptor expression on RA FLS was analyzed by FACS. Cells were stimulated with Lice or TNF alpha and proliferation was measured by [3H]thymidine incorporation and secretion of inflammatory cytokines and metalloproteinase 3 by ELISA. Activation of MAP kinases and Akt was analyzed by Western blotting. Nuclear translocation of NF kappa B was visualized by immunofluorescence. Results: 60-80% and 30-50% of the RA FLS tested expressed TNF receptors I and II, respectively, and 70-75% expressed HVEM. LTa induced RA FLS proliferation at the same level of TNF alpha, which was blocked by etanercept. Both LTa and TNF alpha induced activation of MAP kinases ERK1/2 and p38 as well as Akt. 95-98% of FLS showed nuclear translocation of NF kappa B after stimulation with either cytokines. Lice and TNF alpha were potent to induce secretion of IL-6, IL-8 and metalloproteinase 3 in FLS. Conclusion: LTa is as effective as TNF alpha in stimulating RA FLS. Blocking both cytokines might allow a better control of inflammation and synovial proliferation in RA. (C) 2010 Elsevier Ltd. All rights reserved.
引用
收藏
页码:207 / 214
页数:8
相关论文
共 35 条
[1]   CYTOKINES AND CYTOKINE INHIBITORS OR ANTAGONISTS IN RHEUMATOID-ARTHRITIS [J].
AREND, WP ;
DAYER, JM .
ARTHRITIS AND RHEUMATISM, 1990, 33 (03) :305-315
[2]   THE AMERICAN-RHEUMATISM-ASSOCIATION 1987 REVISED CRITERIA FOR THE CLASSIFICATION OF RHEUMATOID-ARTHRITIS [J].
ARNETT, FC ;
EDWORTHY, SM ;
BLOCH, DA ;
MCSHANE, DJ ;
FRIES, JF ;
COOPER, NS ;
HEALEY, LA ;
KAPLAN, SR ;
LIANG, MH ;
LUTHRA, HS ;
MEDSGER, TA ;
MITCHELL, DM ;
NEUSTADT, DH ;
PINALS, RS ;
SCHALLER, JG ;
SHARP, JT ;
WILDER, RL ;
HUNDER, GG .
ARTHRITIS AND RHEUMATISM, 1988, 31 (03) :315-324
[3]  
Baldassare A, 2007, ARTHRITIS RHEUM, V56, pS394
[4]   True infliximab resistance in rheumatoid arthritis:: a role for lymphotoxin α? [J].
Buch, MH ;
Conaghan, PG ;
Quinn, MA ;
Bingham, SJ ;
Veale, D ;
Emery, P .
ANNALS OF THE RHEUMATIC DISEASES, 2004, 63 (10) :1344-1346
[5]   Targeted depletion of lymphotoxin-α-expressing TH1 and TH17 cells inhibits autoimmune disease [J].
Chiang, Eugene Y. ;
Kolumam, Ganesh A. ;
Yu, Xin ;
Francesco, Michelle ;
Ivelja, Sinisa ;
Peng, Ivan ;
Gribling, Peter ;
Shu, Jean ;
Lee, Wyne P. ;
Refino, Canio J. ;
Balazs, Mercedesz ;
Paler-Martinez, Andres ;
Nguyen, Allen ;
Young, Judy ;
Barck, Kai H. ;
Carano, Richard A. D. ;
Ferrando, Ron ;
Diehl, Lauri ;
Chatterjea, Devavani ;
Grogan, Jane L. .
NATURE MEDICINE, 2009, 15 (07) :766-U10
[6]   LOCALIZATION OF TUMOR-NECROSIS-FACTOR RECEPTORS IN THE SYNOVIAL TISSUE AND CARTILAGE PANNUS JUNCTION IN PATIENTS WITH RHEUMATOID-ARTHRITIS - IMPLICATIONS FOR LOCAL ACTIONS OF TUMOR-NECROSIS-FACTOR-ALPHA [J].
DELEURAN, BW ;
CHU, CQ ;
FIELD, M ;
BRENNAN, FM ;
MITCHELL, T ;
FELDMANN, M ;
MAINI, RN .
ARTHRITIS AND RHEUMATISM, 1992, 35 (10) :1170-1178
[7]   LIGHT (TNFSF14), a novel mediator of bone resorption, is elevated in rheumatoid arthritis [J].
Edwards, J. R. ;
Sun, S. G. ;
Locklin, R. ;
Shipman, C. M. ;
Adamopoulos, I. E. ;
Athanasou, N. A. ;
Sabokbar, A. .
ARTHRITIS AND RHEUMATISM, 2006, 54 (05) :1451-1462
[8]   A role for the lymphotoxin/LIGHT axis in the pathogenesis of murine collagen-induced arthritis [J].
Fava, RA ;
Notidis, E ;
Hunt, J ;
Szanya, V ;
Ratcliffe, N ;
Ngam-ek, A ;
de Fougerolles, AR ;
Sprague, A ;
Browning, JL .
JOURNAL OF IMMUNOLOGY, 2003, 171 (01) :115-126
[9]   Evolving concepts of rheumatoid arthritis [J].
Firestein, GS .
NATURE, 2003, 423 (6937) :356-361
[10]  
Firestein GS, 1999, ARTHRITIS RHEUM-US, V42, P609, DOI 10.1002/1529-0131(199904)42:4<609::AID-ANR3>3.0.CO