A potent and selective nonpeptide antagonist of CXCR2 inhibits acute and chronic models of arthritis in the rabbit.
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 (125)I-labeled human IL-8 binding to, and human IL-8-induced calcium mobilization mediated by, rabbit CXCR2 (IC(50) = 40.5 and 7.7 nM, respectively), but not rabbit CXCR1 (IC(50) = >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 (IC(50) = 0.75 nM), suggesting that inhibition of leukocyte migration into the knee joint is a likely mechanism by which the CXCR2 antagonist modulates disease.
Podolin
Patricia L
PL
Respiratory and Inflammation Center of Excellence for Drug Discovery, Seattle, WA 98108, USA. patty_podolin@gsk.com
Bolognese
Brian J
BJ
Foley
James J
JJ
Schmidt
Dulcie B
DB
Buckley
Peter T
PT
Widdowson
Katherine L
KL
Jin
Qi
Q
White
John R
JR
Lee
Judithann M
JM
Goodman
Richard B
RB
Hagen
Tonja R
TR
Kajikawa
Osamu
O
Marshall
Lisa A
LA
Hay
Douglas W P
DW
Sarau
Henry M
HM
D000208:Acute Disease; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000209:etiology / Q000276:immunology* / Q000517:prevention & control*; D001172:Arthritis, Rheumatoid / Q000209:etiology / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D002908:Chronic Disease; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D016209:Interleukin-8 / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D011817:Rabbits; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016209:Interleukin-8; D008070:Lipopolysaccharides; C469668:N-(3-(aminosulfonyl)-4-chloro-2-hydroxyphenyl)-N'-(2,3-dichlorophenyl)urea; D023063:Receptors, Interleukin-8B; D011994:Recombinant Proteins; D014508:Urea; D010047:Ovalbumin