The effect of a T cell-specific NF-κB inhibitor on in vitro cytokine production and collagen-induced arthritis

被引:97
作者
Gerlag, DM
Ransone, L
Tak, PP
Han, ZN
Palanki, M
Barbosa, MS
Boyle, D
Manning, AM
Firestein, GS
机构
[1] Univ Calif San Diego, Sch Med, Div Rheumatol Allergy & Immunol 0656, La Jolla, CA 92093 USA
[2] Signal Pharmaceut, San Diego, CA 92121 USA
关键词
D O I
10.4049/jimmunol.165.3.1652
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
NF-kappa B plays a key role in the production of cytokines in inflammatory diseases. The effects of a novel T cell-specific NF-kappa B inhibitor, SP100030, were evaluated in cultured Jurkat cells and in murine collagen-induced arthritis (CIA), Chemical libraries were screened for NF-kappa B-inhibitory activity. SP100030, a compound identified in this process, inhibited NP-kappa B activation in PMA/PHA-activated Jurkat cells by EMSA at a concentration of 1 mu M. Jurkat cells and the monocytic cell line THP-1 were transfected with an NF-kappa B promotor/luciferase construct and activated, SP100030 inhibited luciferase production in the Jurkat cells (IC50 = 30 nM), ELISA and RT-PCR confirmed that IL-2, IL-8, and TNF-alpha production by activated Jurkat and other T cell lines were inhibited by SP100030, However, cytokine expression was not blocked by the compound in THP-1 cells, fibroblasts, endothelial cells, or epithelial cells. Subsequently, DBA/1J mice were immunized with type II collagen. Treatment with SP100030 (10 mg/kg/day i.p. beginning on day 21) significantly decreased arthritis severity from onset of clinical signs to the end of the study on day 34 (arthritis score, 5.6 +/- 1.7 for SP100030 and 9.8 +/- 1.5 for control; p < 0.001). Histologic evaluation demonstrated a trend toward improvement in SP100030-treated animals. EMSA of arthritic mouse ankles in CIA showed that synovial NF-kappa B binding was suppressed in the SP100030-treated mice. SP100030 inhibits NF-kappa B activation in T cells, resulting in reduced NF-kappa B-regulated gene expression and decreased CIA. Its selectivity for T cells could provide potent immunosuppression with less toxicity than other NF-kappa B inhibitors.
引用
收藏
页码:1652 / 1658
页数:7
相关论文
共 31 条
[1]  
Aupperle KR, 1999, J IMMUNOL, V163, P427
[2]   Anti-inflammatory actions of glucocorticoids: molecular mechanisms [J].
Barnes, PJ .
CLINICAL SCIENCE, 1998, 94 (06) :557-572
[3]   Mechanisms of disease - Nuclear factor-kappa b - A pivotal transcription factor in chronic inflammatory diseases [J].
Barnes, PJ ;
Larin, M .
NEW ENGLAND JOURNAL OF MEDICINE, 1997, 336 (15) :1066-1071
[4]   Defining therapeutic targets by using adenovirus:: Blocking NF-κB inhibits both inflammatory and destructive mechanisms in rheumatoid synovium but spares anti-inflammatory mediators [J].
Bondeson, J ;
Foxwell, B ;
Brennan, F ;
Feldmann, M .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (10) :5668-5673
[5]  
BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
[6]  
Burger D, 1998, ARTHRITIS RHEUM, V41, P1748, DOI 10.1002/1529-0131(199810)41:10<1748::AID-ART7>3.3.CO
[7]  
2-V
[8]  
DAYER JM, 1994, EUR CYTOKINE NETW, V5, P563
[9]   RANDOMIZED DOUBLE-BLIND COMPARISON OF CHIMERIC MONOCLONAL-ANTIBODY TO TUMOR-NECROSIS-FACTOR-ALPHA (CA2) VERSUS PLACEBO IN RHEUMATOID-ARTHRITIS [J].
ELLIOTT, MJ ;
MAINI, RN ;
FELDMANN, M ;
KALDEN, JR ;
ANTONI, C ;
SMOLEN, JS ;
LEEB, B ;
BREEDVELD, FC ;
MACFARLANE, JD ;
BIJL, H ;
WOODY, JN .
LANCET, 1994, 344 (8930) :1105-1110
[10]   SYNOVIAL INTERLEUKIN-1 RECEPTOR ANTAGONIST AND INTERLEUKIN-1 BALANCE IN RHEUMATOID-ARTHRITIS [J].
FIRESTEIN, GS ;
BOYLE, DL ;
YU, C ;
PAINE, MM ;
WHISENAND, TD ;
ZVAIFLER, NJ ;
AREND, WP .
ARTHRITIS AND RHEUMATISM, 1994, 37 (05) :644-652