An Antagonist of Monocyte Chemoattractant Protein 1 (MCP-1) Inhibits Arthritis in the MRL-lpr Mouse Model

Abstract

An antagonist of human monocyte chemoattractant protein (MCP)-1, which consists of MCP-1(9-76), had previously been characterized and shown to inhibit MCP-1 activity in vitro. To test the hypothesis that, by inhibiting endogenous MCP-1, the antagonist has antiinflammatory activity in vivo, we examined its effect in the MRL-lpr mouse model of arthritis. This strain spontaneously develops a chronic inflammatory arthritis that is similar to human rheumatoid arthritis. Daily injection of the antagonist, MCP-1(9-76), prevented the onset of arthritis as monitored by measuring joint swelling and by histopathological evaluation of the joints. In contrast, controls treated with native MCP-1 had enhanced arthritis symptoms, indicating that the inhibitory effect is specific to the antagonist. In experiments where the antagonist was given only after the disease had already developed, there was a marked reduction in symptoms and histopathology, although individuals varied in the magnitude of the response. The mechanism of inhibition of disease is not known, although the results suggest that it could be more complex than the competitive inhibition of ligand binding that is observed in vitro. The demonstration of the beneficial effects of an MCP-1 antagonist in arthritis suggests that chemokine receptor antagonists could have therapeutic application in inflammatory diseases.

MicroRNA‐124a is a key regulator of proliferation and monocyte chemoattractant protein 1 secretion in fibroblast‐like synoviocytes from patients with rheumatoid arthritis

“…The pivotal role played by MCP-1 in RA in humans is highlighted by the findings of enhanced production of MCP-1 in serum and/or synovial fluid from patients with RA (33)(34)(35). Moreover, data from studies of animal models suggest that MCP-1 is involved in the pathogenesis of RA (36)(37)(38), and MCP-1 was recently reported to be a sensitive marker of disease activity in patients with juvenile RA (39). MCP-1 attracts memory T lymphocytes and natural killer cells, which are major contributors to the pathogenesis of RA (40).…”

Isolation and Structures of Novel Fungal Metabolites as Chemokine Receptor (CCR2) Antagonists

“…Bioassay guided fractionation of three of the extracts led to the discovery of a number of compounds dominated by bisthiodiketopiperazines. These include compounds of the emestrin family including emestrin (1), emestrin C (MPC1001, 2), emestrin D (MPC1001D, 3), two new members named herein as emestrin E (4), secoemestrin C 1 (5), and chaetomin (6) (Figure 1). Similar fractionation of the fourth extract led to the isolation of cytochalasins A (7) and B (8), the only compounds isolated in this program that did not contain the bis-thiodiketopiperazine unit.…”

“…Sterile mycelia was isolated from a soil sample collected in Argentina and grown on a liquid medium which was extracted by MEK and chromatographed on reverse phase HPLC affording 77 mg/liter of chaetomin (6). The structure was confirmed by comparison of 1 H, 13 C NMR spectra and specific rotation of chaetomin that is reported to be a toxic bacteriostatic agent [12].…”

“…The biological significance of MCP-1/CCR2 association in these systems has been recently reviewed [1ϳ5]. Neutralization of CCR2 with either a peptide or small molecule receptor antagonist results in the suppression or prevention of joint swelling in rodent models of rheumatoid arthritis [6,7]. Our expectation is that a small molecule non-peptide antagonist of the MCP-1 binding to CCR2 may have a beneficial therapeutic effect against many of these disease targets.…”

Induction of a CXCL8 binding site on endothelial syndecan‐3 in rheumatoid synovium

“…Chemokines produced by joint tissue cells are biologically active and can stimulate leukocyte migration. The functional importance of these cytokines and their receptors in joint inflammation has been shown in animal models of RA, in which antibodies to these mediators or receptor antagonists significantly reduce the number of leukocytes recruited and the severity of disease (26)(27)(28). In addition, administration of chemokines to the joints in animal models of RA results in inflammation and leukocyte recruitment (29).…”