A variety of cytokines and immunologically relevant surface molecules are expressed by normal human skeletal muscle cells under proinflammatory stimuli

Abstract

SUMMARYMuscle is an attractive target for gene therapy and for immunization with DNA vaccines and is also the target of immunological injury in myositis. It is important therefore to understand the immunologic capabilities of muscle cells themselves. In this study, we show that proinflammatory stimuli induce the expression of other cytokines such as IL-6, transforming growth factor-beta (TGF-b), and granulocytemacrophage colony-stimulating factor (GM-CSF) by muscle cells themselves, as well as the upregulation of human leucocyte antigen (HLA) class I, class II and intercellular adhesion molecule-1 (ICAM-1). Thus, muscle cells have an inherent ability to express and respond to a variety of cytokines and chemokines. The levels of HLA class I, class II and ICAM-1 in inflamed muscle may be affected by the secreted products of the stimulation.

Skeletal muscle cells: from local inflammatory response to active immunity

“…46 ICAM-1 can be shed by the cells and detected as a soluble plasma molecule (sICAM-1). 47 The production of both forms is upregulated in human myoblasts on stimulation with IL-1b, IL-4, IL-6, IFN-g and LPS ( Figure 2a); 42,48 increased levels of sICAM-1 have been detected in the plasma of patients with idiopathic inflammatory myopathies. 49 The binding of sICAM-1 to LFA-1-expressing cells can modulate immune functions through the inhibition of T-cell interactions with APC or target cells.…”

“…1, 38,42 Intercellular adhesion molecule-1 (ICAM-1) molecules, whose ligand on T cells is LFA-1, are commonly present not only on professional APC, such as macrophages and DCs, but also on target cells involved in inflammatory processes. 43 They are absent in normal muscles, but are observed in all inflammatory myopathies, where they are expressed not only by the endothelium of perimysial arterioles and venules, but also by muscle fibres, especially the non-necrotic ones, which are invaded by mononuclear cells.…”

“…Myoblast IL-6 production is increased by TNF-a, IL-1a, IL-1b, LPS, and IFN-g (Figure 3a). 21,42 Human in vitro myoblasts, thanks to membrane-bound glycoprotein130 (gp130), the transducing element of IL-6R, could trigger an autocrine loop in which they respond to self-produced IL-6 through sIL-6R. By using this mechanism, called trans-signalling, they also produce MCP-1 and upregulate membrane bound and soluble ICAM-1 molecules.…”

“…1,44,73 IFN-g stimulation, alone or in combination with TNF-a, induces the expression of HLA-DR, and later of HLA-DP and -DQ too, on cultured human myoblasts. 42,74 Thanks to this, human myoblasts are considered non-professional APCs, with the capacity to drive activation and proliferation of CD4 + T cell lines, previously primed for exogenous and endogenous peptides (Figure 4a). 75,76 According to the two-signal model of T-cell activation, many reports have been devoted to the investigation of muscle cell repertoire of co-stimulatory molecules: no B7-1 (CD80) or B7-2 (CD86) expression was found either in cultured myoblasts under cytokine stimulation or in inflammatory muscle lesions, 48 while the expression of a yet unidentified B7-related co-stimulatory molecule (BB-1) in muscle fibres of myositis and in muscle cells in vitro has been reported, but its importance in costimulation is still uncertain.…”

An analysis of the sensitivity and specificity of MHC-I and MHC-II immunohistochemical staining in muscle biopsies for the diagnosis of inflammatory myopathies

“…MHC-I molecules are necessary for antigen-specific T cell-mediated cytotoxicity and can mediate a response against surface antigens on myofibres [10]. Previous studies have also shown that MHC-I can behave as a pathogenic molecule in its own right since its expression can precede lymphocytic cell infiltration, and transgenic mice overexpressing MHC-I have been shown to develop a severe myopathy even in the absence of inflammation [11][12][13][14].…”