Amelioration of rat adjuvant-induced arthritis by Met-RANTES.
OBJECTIVE
CC chemokines and their receptors play a fundamental role in trafficking and activation of leukocytes at sites of inflammation, contributing to joint damage in rheumatoid arthritis. Met-RANTES, an amino-terminal-modified methionylated form of RANTES (CCL5), antagonizes the binding of the chemokines RANTES and macrophage inflammatory protein 1alpha (MIP-1alpha; CCL3) to their receptors CCR1 and CCR5, respectively. The aim of this study was to investigate whether Met-RANTES could ameliorate adjuvant-induced arthritis (AIA) in the rat.


METHODS
Using immunohistochemistry, enzyme-linked immunosorbent assay, real-time reverse transcription-polymerase chain reaction, Western blot analysis, adoptive transfer, and chemotaxis, we defined joint inflammation, bony destruction, neutrophil and macrophage migration, Met-RANTES binding affinity to rat receptors, proinflammatory cytokine and bone marker levels, CCR1 and CCR5 expression and activation, and macrophage homing into joints with AIA.


RESULTS
Administration of Met-RANTES as a preventative reduced the severity of joint inflammation. Administration of Met-RANTES to ankles with AIA showed decreases in inflammation, radiographic soft tissue swelling, and bone erosion. Met-RANTES significantly reduced the number of neutrophils and macrophages at the peak of arthritis compared with saline-injected controls. Competitive chemotaxis in peripheral blood mononuclear cells demonstrated that Met-RANTES inhibited MIP-1alpha and MIP-1beta at 50% inhibition concentrations of 5 nM and 2 nM, respectively. Furthermore, levels of tumor necrosis factor alpha, interleukin-1beta, macrophage colony-stimulating factor, and RANKL were decreased in joints with AIA in the Met-RANTES group compared with the control group. Interestingly, the expression and activation of CCR1 and CCR5 in the joint were down-regulated in the Met-RANTES group compared with the control group. Functionally, Met-RANTES administration decreased adoptively transferred peritoneal macrophage homing into the joint.


CONCLUSIONS
The data suggest that the targeting of Th1-associated chemokine receptors reduce joint inflammation, bone destruction, and cell recruitment into joints with AIA.
Shahrara
Shiva
S
Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA. s-shahrara@northwestern.edu
Proudfoot
Amanda E I
AE
Woods
James M
JM
Ruth
Jeffrey H
JH
Amin
M Asif
MA
Park
Christy C
CC
Haas
Christian S
CS
Pope
Richard M
RM
Haines
G Kenneth
GK
Zha
Yuan Yuan
YY
Koch
Alisa E
AE
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology; D018946:Chemokine CCL5 / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019742:Chemokines, CC / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051381:Rats; D019707:Receptors, Chemokine / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology
D018946:Chemokine CCL5; D019742:Chemokines, CC; C108335:RANTES, Met-; D019707:Receptors, Chemokine