Inhibition of monocyte chemoattractant protein-1 ameliorates rat adjuvant-induced arthritis.
Chemokines, including RANTES/CCL5 and MCP-1/CCL2, are highly expressed in the joints of patients with rheumatoid arthritis, and they promote leukocyte migration into the synovial tissue. This study was conducted to determine whether the inhibition of RANTES and MCP-1 therapeutically was capable of ameliorating rat of adjuvant-induced arthritis (AIA). Postonset treatment of AIA using a novel inhibitor for endogenous MCP-1 (P8A-MCP-1) improved clinical signs of arthritis and histological scores measuring joint destruction, synovial lining, macrophage infiltration, and bone erosion. Using immunohistochemistry, ELISA, real-time RT-PCR, and Western blot analysis, we defined joint inflammation, bony erosion, monocyte migration, proinflammatory cytokines, and bone markers, and p-p38 levels were reduced in rat AIA treated with P8A-MCP-1. In contrast, neither the dominant-negative inhibitor for endogenous RANTES (44AANA47-RANTES) nor the CCR1/CCR5 receptor antagonist, methionylated-RANTES, had an effect on clinical signs of arthritis when administered after disease onset. Additionally, therapy with the combination of 44AANA47-RANTES plus P8A-MCP-1 did not ameliorate AIA beyond the effect observed using P8A-MCP-1 alone. Treatment with P8A-MCP-1 reduced joint TNF-alpha, IL-1beta, and vascular endothelial growth factor levels. P8A-MCP-1 also decreased p38 MAPK activation in the joint. Our results indicate that inhibition of MCP-1 with P8A-MCP-1 after the onset of clinically detectable disease ameliorates AIA and decreases macrophage accumulation, cytokine expression, and p38 MAPK activation within the joint.
Shahrara
Shiva
S
Department of Medicine, Division of Rheumatology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA. s-shahrara@northwestern.edu
Proudfoot
Amanda E I
AE
Park
Christy C
CC
Volin
Michael V
MV
Haines
G Kenneth
GK
Woods
James M
JM
Aikens
Christopher H
CH
Handel
Tracy M
TM
Pope
Richard M
RM
D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000037:antagonists & inhibitors; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D002464:Cell Migration Inhibition / Q000276:immunology; D018932:Chemokine CCL2 / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D018946:Chemokine CCL5 / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000502:physiology; D003094:Collagen / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D018450:Disease Progression; D005260:Female; D007274:Injections, Intraperitoneal; D009154:Mutation; D051381:Rats; D011917:Rats, Inbred Lew; D012720:Severity of Illness Index; D013997:Time Factors
D000276:Adjuvants, Immunologic; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D018946:Chemokine CCL5; C108335:RANTES, Met-; D003094:Collagen