Amelioration of rat adjuvant‐induced arthritis by Met‐RANTES

Abstract

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 RAN-TES (CCL5), antagonizes the binding of the chemokines RANTES and macrophage inflammatory protein 1␣ (MIP-1␣; CCL3) to their receptors CCR1 and CCR5, respectively. The aim of this study was to investigate whether Met-RANTES could ameliorate adjuvantinduced arthritis (AIA) in the rat.Methods. Using immunohistochemistry, enzymelinked 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 salineinjected controls. Competitive chemotaxis in peripheral blood mononuclear cells demonstrated that Met-RANTES inhibited MIP-1␣ and MIP-1␤ at 50% inhibition concentrations of 5 nM and 2 nM, respectively. Furthermore, levels of tumor necrosis factor ␣, interleukin-1␤, 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.Conclusion. The data suggest that the targeting of Th1-associated chemokine receptors reduce joint inflammation, bone destruction, and cell recruitment into joints with AIA.

Celastrus and Its Bioactive Celastrol Protect against Bone Damage in Autoimmune Arthritis by Modulating Osteoimmune Cross-talk

“…Regulation of bone resorption by osteoclasts is essentially mediated via the RANKL/RANK/OPG system (8,9,11,24,43). We observed that celastrus/celastrol-treated rats had a decrease in serum RANKL levels along with a reduction in RANKL/OPG ratio compared with the control rats.…”

Epigallocatechin-3-gallate inhibits IL-6 synthesis and suppresses transsignaling by enhancing soluble gp130 production

“…EGCG was brought into suspension in PBS. EGCG (100 mg/kg) or PBS was administered i.p., with treatment initiated on day 7 after arthritis induction when the first signs of joint inflammation and pain are usually noted and continued until day 16 (46,47). On day 17, animals were anesthetized for blood collection by cardiac puncture and then killed for biochemical and cytokine analysis.…”

Inhibition of Monocyte Chemoattractant Protein-1 Ameliorates Rat Adjuvant-Induced Arthritis

“…Clinical parameters measured included articular index (AI) score and ankle circumference, as previously described (20). AI scores were recorded for each ankle joint by a consistent observer blinded to the treatment received by the animals.…”

“…Therapeutic intervention before disease onset using CCR1 and CCR5 inhibitors reduces joint inflammation, bone erosion, proinflammatory cytokines, and monocyte and neutrophil recruitment in experimental arthritis (20,21). We are not aware of studies that have examined the inhibition of RANTES, initiated after the onset of clinical disease.…”

“…-RANTES was chosen based on the in vivo dose response performed for cell recruitment in the peritoneum and the dosage of Met-RANTES was chosen based on our previous study, which demonstrated amelioration of AIA when used preventatively (20). Tissues were harvested from each group on days 0, 21, and 28 postadjuvant for ELISA, Western blot, mRNA, and immunohistochemical studies.…”