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

Abstract

Mast cells are key effectors in the pathogenesis of inflammatory and tissue destructive diseases such as rheumatoid arthritis (RA). These cells contain specialized secretory granules loaded with bioactive molecules including cytokines, growth factors, and proteases that are released upon activation. This study investigated the regulation of matrix metalloproteinase MMP-9 (gelatinase B) in human mast cells by cytokines that are known to be involved in the pathogenesis of RA. Immunohistochemical staining of synovial tissue showed abundant expression of MMP-9 by synovial tissue mast cells in patients with RA but not in normal controls. The expression, activity, and production of MMP-9 in mast cells was confirmed by RT-PCR, zymography, and Western blotting using cord blood-derived human mast cells (CB-HMC). Treatment of CB-HMC with TNF-α significantly increased the expression of MMP-9 mRNA and up-regulated the activity of MMP-9 in a time- and dose-dependent manner. By contrast, IFN-γ inhibited MMP-9 mRNA and protein expression. The cytokine-mediated regulation of MMP-9 was also apparent in the human mast cell line (HMC-1) and in mouse bone marrow-derived mast cells. Furthermore, TNF-α significantly increased the invasiveness of CB-HMC across Matrigel-coated membranes while the addition of IFN-γ, rTIMP-1, or pharmacological MMP inhibitors significantly reduced this process. These observations suggest that MMP-9 is not a stored product in mast cells but these cells are capable of producing this enzyme under inflammatory conditions that may facilitate the migration of mast cell progenitors to sites of inflammation and may also contribute to local tissue damage.

Decreased number of mast cells infiltrating into needle biopsy specimens leads to a better prognosis of prostate cancer

“…These factors are all involved both in normal as well as tumour-associated angiogenesis. In addition to these angiogenic factors, mast cells also produce proteolytic enzymes such as matrix metalloproteinase (MMP)-2 and -9, and tryptase (Fang et al, 1999;Vincent et al, 2000;Di Girolamo et al, 2006). These factors are known to promote invasion of cancer cells into interstitial stromal tissue.…”

Differential regulation of matrix metalloproteinase 2 and matrix metalloproteinase 9 by activated protein C: Relevance to inflammation in rheumatoid arthritis

“…The importance of this enzyme in arthritis is highlighted by the finding that MMP-9-knockout mice display less severe antibodyinduced arthritis than do wild-type mice (10). MMP-9 is implicated in the degradation of basement membrane collagen, synovial membrane neovascularization, transfer of endothelial and hemopoietic stem cells from a quiescent to a proliferative state, and promotion of leukocyte migration from the vascular compartment to sites of inflammation (7,(35)(36)(37). In the RA synovial joint, levels of leukocyte-derived MMP-9 are directly related to the degree of inflammation.…”

Role of osteopontin in induction of monocyte chemoattractant protein 1 and macrophage inflammatory protein 1β through the NF‐κB and MAPK pathways in rheumatoid arthritis

“…In addition, there are other proinflammatory molecules that act in synergy with chemokines to promote leukocyte migration in autoimmune arthritis, including matrix metalloproteinase and osteopontin (OPN) (14,15). However, the mechanism of interaction of these molecules in an inflammatory milieu, which helps perpetuate local inflammation in the joint, is not understood.…”