Tumor necrosis factor-alpha-converting enzyme is expressed in the inflamed peripheral nervous system.

Tumor necrosis factor-alpha (TNF-alpha) is considered to play a critical role in the pathogenesis of immune-mediated inflammatory demyelinating disorders of the peripheral nervous system (PNS). Processing of membrane-bound inactive pro-TNF-alpha into the active soluble cytokine is mediated by a sheddase, the so-called TNF-alpha-converting enzyme (TACE), a member of the A Disintegrin and Metalloproteinase (ADAM) family. We explored the expression of TACE (ADAM-17) in sciatic nerves from Lewis rats with experimental autoimmune neuritis (EAN), an animal model of the Guillain-Barré syndrome (GBS), an immune-mediated polyradiculoneuropathy. To extend our study to human disease, sural nerve biopsies from GBS patients were investigated by immunohistochemistry. In EAN, T lymphocytes could be defined as the cellular source of ADAM-17 with peak expression levels at maximum clinical disease severity. Similarly, in human sural nerves, ADAM-17-expressing T cells could be localized primarily within the epi- and perineurium, whereas in control sections from patients with non-inflammatory neuropathies, no expression could be depicted. Our findings indicate that ADAM-17 is upregulated during EAN and expressed in nerves of GBS patients and thus may contribute to the pathogenesis of inflammatory demyelination of the PNS.

ADAM-10 and ADAM-17 in the inflamed human CNS.

Inflammatory demyelinating disorders of the CNS, such as multiple sclerosis (MS), are mediated, at least in part, by various cytokines and proteases. In the present study, we investigated the expression of A disintegrin and metalloproteinase (ADAM)-17, an important sheddase for various proteins, including tumor necrosis factor-alpha (TNF-alpha), and the p75- and p55-TNF receptors, as well as ADAM-10, a protease implicated in myelin degradation, in post mortem CNS tissue samples from patients with MS, and normal brain tissue (as control) by immunohistochemistry. ADAM-10 was found to be expressed by astrocytes in all MS and control sections studied; however, in some MS sections, perivascular macrophages were determined as an additional cellular source as well. ADAM-17 could be observed exclusively in acute and chronic active MS plaques and localized to invading T lymphocytes. The staining pattern of ADAM-17 in MS plaques was mirrored in distribution and extent by the pattern obtained with an antibody against the p75-TNF-receptor (TNFR-2), whereas TNF-alpha was found to be expressed primarily by perivascular macrophages. In studying cerebrospinal fluid (CSF) samples from MS patients, we were able to detect increased protein levels of ADAM-17 as compared with noninflammatory controls. In addition, increased levels of soluble TNFR-2 could be measured, suggestive of an active shedding process mediated by ADAM-17. The stimulation of peripheral blood mononuclear cells (PBMC) obtained from MS patients and healthy individuals corroborated these findings by revealing expression of ADAM-17 by T lymphocytes and ADAM-10 by macrophages in vitro. Our results indicate that ADAM-10 is expressed constitutively by astrocytes in the normal and inflamed human CNS. In contrast, under inflammatory conditions, ADAM-10, expressed by perivascular macrophages, and ADAM-17, expressed by invading T cells, may actively contribute to the pathogenesis of inflammatory disorders of the CNS.