Pharmacological blockade of CCR1 ameliorates murine arthritis and alters cytokine networks in vivo.
OBJECTIVE
The chemokine receptor CCR1 is a potential target for the treatment of rheumatoid arthritis. To explore the impact of CCR1 blockade in experimental arthritis and the underlying mechanisms, we used J-113863, a non-peptide antagonist of the mouse receptor.


METHODS
Compound J-113863 was tested in collagen-induced arthritis (CIA) and three models of acute inflammation; Staphylococcus enterotoxin B (SEB)-induced interleukin-2 (IL-2), delayed-type hypersensitivity (DTH) response, and lipopolysaccharide (LPS)-induced tumour necrosis factoralpha (TNFalpha) production. In the LPS model, CCR1 knockout, adrenalectomised, or IL-10-depleted mice were also used. Production of TNFalpha by mouse macrophages and human synovial membrane samples in vitro were also studied.


RESULTS
Treatment of arthritic mice with J-113863 improved paw inflammation and joint damage, and dramatically decreased cell infiltration into joints. The compound did not inhibit IL-2 or DTH, but reduced plasma TNFalpha levels in LPS-treated mice. Surprisingly, CCR1 knockout mice produced more TNFalpha than controls in response to LPS, and J-113863 decreased TNFalpha also in CCR1 null mice, indicating that its effect was unrelated to CCR1. Adrenalectomy or neutralisation of IL-10 did not prevent inhibition of TNFalpha production by J-113863. The compound did not inhibit mouse TNFalpha in vitro, but did induce a trend towards increased TNFalpha release in cells from synovial membranes of rheumatoid arthritis patients.


CONCLUSIONS
CCR1 blockade improves the development of CIA, probably via inhibition of inflammatory cell recruitment. However, results from both CCR1-deficient mice and human synovial membranes suggest that, in some experimental settings, blocking CCR1 could enhance TNF production.
Amat
M
M
Department of Biology, Drug Discovery, Almirall Research Center, Sant Feliu de Llobregat, Barcelona, Spain.
Benjamim
C F
CF
Williams
L M
LM
Prats
N
N
Terricabras
E
E
Beleta
J
J
Kunkel
S L
SL
Godessart
N
N
D000818:Animals; D001168:Arthritis / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014966:Xanthenes / Q000493:pharmacokinetics / Q000627:therapeutic use*
C515300:CCR1 protein, human; C515301:Ccr1 protein, mouse; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha; D014966:Xanthenes; C413447:UCB 35625