The cell-specific expression of metalloproteinase-disintegrins (ADAMs) in inflammatory myopathies

Abstract

Inflammatory cell invasion and cytokine activation are important steps in the pathogenesis of immune-mediated diseases of muscle. Metalloproteinase-disintegrins (ADAMs) are considered to play a critical role in leukocyte migration by promoting cellular adhesion, cleavage of molecules of the extracellular matrix and shedding of membrane bound cytokines. Here, we report the expression patterns of ADAM8, ADAM9, ADAM10, ADAM12, ADAM17 and ADAM19 in cultured human myoblasts and peripheral blood mononuclear cells (PBMCs) in vitro, as well as in biopsies from patients suffering from polymyositis (PM), dermatomyositis (DM), inclusion body myositis (IBM) and non-inflammatory controls. We observed an in vitro downregulation of the RNAs of ADAM10, ADAM17 and ADAM19 in myoblasts after stimulation with various pro- and anti-inflammatory mediators, whereas in PBMCs an RNA upregulation of ADAM9, ADAM10, ADAM17 and ADAM19 was detectable under identical conditions. In human muscle biopsies, invading CD3+ T lymphocytes expressed ADAM17 and ADAM19, whereas macrophages co-localized to ADAM8, as detected by immunohistochemistry. Transfection of PBMCs with ADAM19 single interfering RNA and incubation with a metalloproteinase inhibitor suggest proteolytic activity of ADAM19 and involvement in the shedding of tumor necrosis factor-alpha. No differences in the cellular expression profiles between PM, DM and IBM were found, whereas the sections from non-inflammatory controls did not reveal any positive immunoreactivity for ADAMs, except for ADAM10, which is localized exclusively to muscle fibres. Our results suggest that certain ADAMs are expressed by specific cell populations during the genesis of immune-mediated diseases of human muscle.