title: Upregulation and interaction of TNFalpha and gelatinases A and B in painful peripheral nerve injury.
abstract: Chronic constriction injury (CCI) to peripheral nerve causes a painful neuropathy in association with a process of axonal degeneration and endoneural remodeling that involves macrophage recruitment and local increase in extracellular proteases and tumor necrosis factor alpha (TNF-alpha). Cell surface activation of TNF-alpha from its transmembrane precursor, as well as sequestration of TNF-alpha receptors II and I, is performed by the zinc-dependent endopeptidase family of matrix metalloproteinases (MMPs). Among TNF-alpha-converting MMPs, basal lamina degrading gelatinases are thought to play a role in sciatic nerve injury. In the present study, we determined the forms of TNF-alpha involved in the development of CCI neuropathy in rats, using Western blot analysis, and the temporal correlation of TNF-alpha and TNFRI protein profiles with gelatinases activity at the site of peripheral nerve injury. We observed two peaks in TNF-alpha protein during the first week of CCI that correspond to previously reported peaks in painful behavior. We propose that the first peak at 6 h post-CCI is due to the local expression of the cytotoxic transmembrane 26 kDa TNF-alpha protein released by resident Schwann cells, mast cells and macrophages. This peak in TNF-alpha protein expression corresponds to an increase in gelatinase B (MMP-9) activity, which is greatly upregulated as early as 3 h following CCI to rat sciatic nerve. The second peak occurs at 5 days post-CCI, and may represent TNF-alpha protein released by hematogenously recruited macrophages. This peak is marked by the increase in active soluble 17 kDa TNF-alpha and by gelatinase A (MMP-2) upregulation. These observations suggest that there is a pathogenic role for the TNF-alpha-converting function of MMP-2 in painful CCI neuropathy. We conclude that severe nerve injury induces MMPs, TNF-alpha and TNFRI, which interactively control the privileged endoneurial environment and the pathogenesis of the painful neuropathies associated with the macrophage-dependent processes of Wallerian degeneration.
authors.affiliation: Department of Anesthesiology, University of California, 9500 Gilman Dr., La Jolla, San Diego, CA 92093 0629, USA. vshubayev@ucsd.edu
authors.forename: V I
authors.initials: VI
authors.lastname: Shubayev
authors.forename: R R
authors.initials: RR
authors.lastname: Myers
mesh_terms: D000818:Animals; D001369:Axons / Q000737:chemistry / Q000201:enzymology / Q000276:immunology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D010525:Peripheral Nerves / Q000201:enzymology / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D012584:Sciatic Nerve / Q000201:enzymology / Q000276:immunology / Q000293:injuries*; D020426:Sciatic Neuropathy / Q000201:enzymology / Q000276:immunology; D012585:Sciatica / Q000201:enzymology / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014855:Wallerian Degeneration / Q000201:enzymology / Q000276:immunology
chemical_list: D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9