A potent and selective nonpeptide antagonist of CXCR2 inhibits acute and chronic models of arthritis in the rabbit

被引:141
作者
Podolin, PL
Bolognese, BJ
Foley, JJ
Schmidt, DB
Buckley, PT
Widdowson, KL
Jin, Q
White, JR
Lee, JM
Goodman, RB
Hagen, TR
Kajikawa, O
Marshall, LA
Hay, DWP
Sarau, HM
机构
[1] GlaxoSmithKline, Resp & Inflammat Ctr Excellence Drug Discovery, King Of Prussia, PA 19406 USA
[2] GlaxoSmithKline, Dept Prot Agents & Human Gene Therapy, King Of Prussia, PA 19406 USA
[3] GlaxoSmithKline, Project & Portfolio Management, King Of Prussia, PA 19406 USA
[4] Univ Washington, Sch Med, Dept Med, Div Pulm & Crit Care Med, Seattle, WA 98108 USA
关键词
D O I
10.4049/jimmunol.169.11.6435
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Much evidence implicates IL-8 as a major mediator of inflammation and joint destruction in rheumatoid arthritis. The effects of IL-8 and its related ligands are mediated via two receptors, CXCR1 and CXCR2. In the present study, we demonstrate that a potent and selective nonpeptide antagonist of human CXCR2 potently inhibits I-125-labeled human IL-8 binding to, and human IL-8-induced calcium mobilization mediated by, rabbit CXCR2 (IC50 = 40.5 and 7.7 nM, respectively), but not rabbit CXCR1 (IC50 = >1000 and 2200 nM, respectively). These data suggest that the rabbit is an appropriate species in which to examine the anti-inflammatory effects of a human CXCR2-selective antagonist. In two acute models of arthritis in the rabbit induced by knee joint injection of human IL-8 or LPS, and a chronic Ag (OVA)-induced arthritis model, administration of the antagonist at 25 mg/kg by mouth twice a day significantly reduced synovial fluid neutrophils, monocytes, and lymphocytes. In addition, in the more robust LPS- and OVA-induced arthritis models, which were characterized by increased levels of proinflammatory mediators in the synovial fluid, TNF-alpha, IL-8, PGE(2), leukotriene B-4, and leukotriene C-4 levels were significantly reduced, as was erythrocyte sedimentation rate, possibly as a result of the observed decreases in serum TNF-alpha and IL-8 levels. In vitro, the antagonist potently inhibited human IL-8-induced chemotaxis of rabbit neutrophils (IC50 = 0.75 nM), suggesting that inhibition of leukocyte migration into the knee joint is a likely mechanism by which the CXCR2 antagonist modulates disease.
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页码:6435 / 6444
页数:10
相关论文
共 82 条
[1]   The CXC chemokines growth-regulated oncogene (GRO) alpha, GRO beta, GRO gamma, neutrophil-activating peptide-2, and epithelial cell-derived neutrophil-activating peptide-78 are potent agonists for the type B, but not the type A, human interleukin-8 receptor [J].
Ahuja, SK ;
Murphy, PM .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (34) :20545-20550
[2]  
AKAHOSHI T, 1994, LYMPHOKINE CYTOK RES, V13, P113
[3]   RHEUMATOID-ARTHRITIS - RELATION OF SERUM C-REACTIVE PROTEIN AND ERYTHROCYTE SEDIMENTATION-RATES TO RADIOGRAPHIC CHANGES [J].
AMOS, RS ;
CONSTABLE, TJ ;
CROCKSON, RA ;
CROCKSON, AP ;
MCCONKEY, B .
BRITISH MEDICAL JOURNAL, 1977, 1 (6055) :195-197
[4]  
[Anonymous], 1977, Am J Clin Pathol, V68, P505
[5]   Role of cytokines, acute-phase proteins, and chemokines in the progression of rheumatoid arthritis [J].
Badolato, R ;
Oppenheim, JJ .
SEMINARS IN ARTHRITIS AND RHEUMATISM, 1996, 26 (02) :526-538
[6]   INTERLEUKIN-8 AND THE CHEMOKINE FAMILY [J].
BAGGIOLINI, M ;
LOETSCHER, P ;
MOSER, B .
INTERNATIONAL JOURNAL OF IMMUNOPHARMACOLOGY, 1995, 17 (02) :103-108
[7]   A NOVEL NEUTROPHIL CHEMOATTRACTANT GENERATED DURING AN INFLAMMATORY REACTION IN THE RABBIT PERITONEAL-CAVITY INVIVO - PURIFICATION, PARTIAL AMINO-ACID-SEQUENCE AND STRUCTURAL RELATIONSHIP TO INTERLEUKIN-8 [J].
BEAUBIEN, BC ;
COLLINS, PD ;
JOSE, PJ ;
TOTTY, NF ;
HSUAN, J ;
WATERFIELD, MD ;
WILLIAMS, TJ .
BIOCHEMICAL JOURNAL, 1990, 271 (03) :797-801
[8]   DISEASE SEVERITY IN RHEUMATOID-ARTHRITIS - RELATIONSHIPS OF PLASMA TUMOR-NECROSIS-FACTOR-ALPHA, SOLUBLE INTERLEUKIN 2-RECEPTOR, SOLUBLE CD4/CD8 RATIO, NEOPTERIN, AND FIBRIN D-DIMER TO TRADITIONAL SEVERITY AND FUNCTIONAL MEASURES [J].
BECKHAM, JC ;
CALDWELL, DS ;
PETERSON, BL ;
PIPPEN, AMM ;
CURRIE, MS ;
KEEFE, FJ ;
WEINBERG, JB .
JOURNAL OF CLINICAL IMMUNOLOGY, 1992, 12 (05) :353-361
[9]   MOLECULAR CHARACTERIZATION OF THE INTERLEUKIN-8 RECEPTOR [J].
BECKMANN, MP ;
MUNGER, WE ;
KOZLOSKY, C ;
VANDENBOS, T ;
PRICE, V ;
LYMAN, S ;
GERARD, NP ;
GERARD, C ;
CERRETTI, DP .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1991, 179 (02) :784-789