Effects of induced mast cell activation on prostaglandin E and metalloproteinase production by rheumatoid synovial tissue in vitro

Abstract

Objective-To determine whether induced mast cell activation/degranulation in rheumatoid synovial explants modulates the production of prostaglandin E (PGE 2 ), and the matrix metalloproteinases (MMPs) collagenase 1, gelatinase A, and stromelysin 1. Methods-Synovial explant cultures were treated either with rabbit IgG anti-human IgE as a mast cell (MC) secretagogue or with non-immune rabbit IgG as controls. After 20 hours conditioned medium was assayed for the release of MC tryptase, PGE 2 , collagenase 1, gelatinase A, and stromelysin 1 using radioimmunoassay, enzyme linked immunosorbent assay, western blot, and zymogram techniques; tissue explants were examined immunohistologically for the relative distributions of MC tryptase, collagenase 1, and stromelysin 1. Results-Over a 20 hour incubation period the MC secretagogue treated explants showed a significant increase in the quantities of released tryptase and PGE 2 compared with controls. By contrast, the three MMPs showed variable values between experiments in response to MC activation; no reproducible trend of either an increased or decreased production of each MMP over control values was evident. Each MMP initially appeared as an inactive precursor form; collagenase 1 and stromelysin 1 were more eVectively processed to active forms in the MC activated cultures. Immunolocalisation studies of MC activated explants showed that areas of extracellular tryptase were commonly associated with the local production of both collagenase 1 and stromelysin 1. Conclusion-MC degranulation induced artificially in rheumatoid synovial explant cultures consistently resulted in an increased production of PGE 2 but had variable eVects on the quantification of released collagenase 1, gelatinase A, and stromelysin 1. Such observations support the concept that activated synovial MCs within their native environment stimulate the production of non-MC derived PGE 2 and may contribute to the regulation and processing of specific MMPs; both aspects represent important components of the inflammatory and degradative processes of the rheumatoid lesion.

Human Mast Cell β-Tryptase Is a Gelatinase

“…An involvement of mast cells in rheumatoid arthritis has been suggested by numerous studies (33)(34)(35)(36)(37) and was recently supported by a study using mast cell-deficient mice (38). However, the mechanisms underlying the contribution of mast cells to the ECM destruction observed in these cases are not elucidated.…”

Mast Cell Stabilization Reduces Hemorrhage Formation and Mortality After Administration of Thrombolytics in Experimental Ischemic Stroke

“…The integrin-labeled basal lamina loses its integrity very early after the onset of ischemia. 37 Cerebral MCs release chymase, 30,38,39 which cleaves fibronectin and activates procollagenases to liberate MMPs 15,16 even in the presence of the tissue inhibitor of metalloproteinase. 40 MCs also directly release gelatinases A (MMP-2) and B (MMP-9), 41 which are known to degrade collagen type IV.…”

Human Mast Cell-Derived Gelatinase B (Matrix Metalloproteinase-9) Is Regulated by Inflammatory Cytokines: Role in Cell Migration

“…There is considerable circumstantial evidence implicating mast cells in the pathogenesis of human rheumatoid arthritis (RA). These include the production of inflammatory (13,14) and tissue destructive (15,16) mediators. Moreover, a significant increase in mast cell numbers has been documented in human synovial tissue derived from patients with RA (8,9).…”