Cytokine production in muscle tissue of patients with idiopathic inflammatory myopathies

Abstract

Objective. To study cytokine expression in muscle tissues of patients with inflammatory myopathies and to compare the profiles of patients with polymyositis (PM), inclusion body myositis (IBM), and dermatomyositis (DM). Methods. We performed indirect immunohistochemistry studies of muscle tissue sections with a panel of 16 different cytokine‐specific monoclonal antibodies, directed against interleukin‐1α, (IL‐1α), IL‐1β, IL‐1 receptor antagonist (IL‐1ra), IL‐2, IL‐3, IL‐4, IL‐6, IL‐8, IL‐10, IL‐13, interferon‐γ (IFNγ), tumor necrosis factor α (TNFα), granulocyte‐macrophage colonystimulating factor (GM‐CSF), transforming growth factor β1 (TGFß1), TGFß2, and TGFß3 in 5 untreated patients each with PM, DM, and IBM and in 4 normal controls. Fresh frozen muscle tissue sections were fixed in formaldehyde before the procedure. The use of saponin as a detergent to permeabilize the cell membranes enabled identification of intracellular cytokine production. Results. The most prominent finding was the expression of IL‐1α observed in all patients but in none of the normal controls. In all patients with PM, DM, and IBM, IL‐1α was expressed in endothelial cells of capillaries, arterioles, and venules in areas surrounded by inflammatory cells, and also in areas with no or scarce inflammatory cells in both endomysium and perimysium. Furthermore, IL‐1α was also expressed in mononuclear inflammatory cells in all 15 cases. IL‐1β was observed in inflammatory cells in 10 of the 15 patients but, in contrast to IL‐1α, it was not expressed in blood vessel walls. TGFß1, TGFß2, and TGFß3 were strongly positive in all 15 patients, but only scattered cells were positive in the normal controls. The remaining cytokines were observed only in relatively few cells and only in occasional patients (although the patients were selected for the presence of large infiltrates), and in none of the controls. The patterns were similar in PM, DM, and IBM. Conclusion. Cytokine expression in muscle tissue of patients with inflammatory myopathy is dominated by IL‐1α, IL‐1β, and TGFß1–3. The predominant IL‐1α expression in the blood vessels indicates an importance of the endothelial cells in the inflammatory process in PM, IBM, and DM. A sustained, local release of T cell‐derived cytokines may not be a requirement for tissue injury in the inflammatory myopathies. There does not appear to be a qualitative difference in cytokine expression patterns in PM, IBM, and DM.

Skeletal Muscle Fibers Express Major Histocompatibility Complex Class II Antigens Independently of Inflammatory Infiltrates in Inflammatory Myopathies

“…34,35 IL-1␣ is mainly expressed by endothelial cells of capillaries, arterioles, and venules in inflammatory myopathies 36 and IL-1␣ has also been observed in muscle tissue without any infiltration of inflammatory cells. 4 Thus one possibility is that MHC class II and class I expression is regulated in response to IL-1␣.…”

Vascular endothelial growth factor is highly expressed in muscle tissue of patients with polymyositis and patients with dermatomyositis

“…Our hypothesis of local muscle tissue hypoxia is supported by increased expression of interleukin-1␣ (IL-1␣), IL-1␤, transforming growth factor ␤, intercellular adhesion molecule 1, and vascular cellular adhesion molecule 1 in the muscle tissue of patients with myositis (10)(11)(12)(13)(14), because these molecules are known to be up-regulated by hypoxia (10)(11)(12)(13). Moreover, the endothelial cells are frequently thickened, resembling endothelial cells of high endothelium venules (HEV), indicating their activation (3,10,11,(15)(16)(17). Notably, such phenotypically changed endothelial cells were observed in patient muscle tissue irrespective of inflammation (15).…”

“…Moreover, the endothelial cells are frequently thickened, resembling endothelial cells of high endothelium venules (HEV), indicating their activation (3,10,11,(15)(16)(17). Notably, such phenotypically changed endothelial cells were observed in patient muscle tissue irrespective of inflammation (15). Potentially, such phenotypically changed microvessels might affect the local muscular circulation and hence contribute to tissue hypoxia and metabolic alterations.…”

Immune and myodegenerative pathomechanisms in inclusion body myositis

“…An early immunocytochemistry study that evaluated expression of inflammatory mediators in myositis, found predominant presence of IL‐1 α (in endothelial cells), IL‐1 β and TGF‐ β (both in inflammatory cells), albeit no apparent difference in the expression pattern was observed between DM, PM and IBM 147. Similarly, De Bleeker and colleagues detected TNF‐ α in macrophages, endothelial cells, and central myonuclei in IBM, DM, and PM muscle but not in that of nonmyositic controls 148.…”