Abstract
Objectives: Our study sought to elucidate the role of oxidative stress for shedding of tumor necrosis factor-α (TNF-α) and for activating TNF-α-converting enzyme (TACE). Background: TNF-α, a central inflammatory cytokine, is discussed as one of the mediators of reperfusion injury. Shedding of membrane-bound pro-TNF-α is thought to be largely due to TNF-α-converting enzyme (TACE). Methods: Release of TNF-α and TACE dependency were studied in isolated rat hearts and in the human mast cell line HMC-1. Results: In reperfused hearts, interstitial release of TNF-α occurred in two phases (2–10 and >45 min). It depended on the presence of oxygen during reperfusion and was attenuated by reduced glutathione. Infusion of the oxidants H2O2 or HOCl elicited release in non-ischemic hearts. TNF-α release was inhibited in hearts treated with degranulation inhibitors ketotifen or cromoglycate, suggesting mast cells as major source for myocardial TNF-α. This was confirmed by tissue staining. Post-ischemic release of histamine, however, did not parallel that of TNF-α. Heart tissue contained mainly mature TACE. HMC-1 expressed abundant pro-TACE and cleaved the pro-TNF-α-peptide Ac-SPLAQAVRSSSR-NH2. However, cleavage was nonspecific and only partly inhibited by TACE inhibitor TAPI-2 (10–100 μmol/l), while it was stimulated by H2O2 and HOCl and fully blocked by the nonspecific metalloprotease inhibitor o-phenanthroline. Conclusions: The mechanism underlying TNF-α release from post-ischemic myocardium is oxidation-dependent but largely independent of activation of TACE. Mast cell stabilizers may be useful in preventing TNF-α release during reperfusion.
Item Type: | Journal article |
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Form of publication: | Publisher's Version |
Keywords: | Cytokines; Free radicals; Ischemia; Reperfusion |
Faculties: | Medicine |
Subjects: | 500 Science > 540 Chemistry |
URN: | urn:nbn:de:bvb:19-epub-14397-4 |
ISSN: | 0008-6363 |
Language: | English |
Item ID: | 14397 |
Date Deposited: | 24. Jan 2013, 11:04 |
Last Modified: | 04. Nov 2020, 12:54 |