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Several clinical studies suggested that EMD may also improve gingival healing after periodontal surgery and thus affect the fate of gingival fibroblasts (GFs). Since these cells are targets for local inflammatory mediators such as TNF, a pro\u2010apoptotic cytokine, during the course of periodontal disease, we tested whether EMD protects human GFs (hGFs) from TNF\u2010induced cytotoxicity. Quiescent primary hGFs were challenged with TNF (10\u2013100 ng\/ml) with or without EMD (100 \u00b5g\/ml) pretreatment. Cell viability was assessed by neutral red staining, cell death by LDH release and apoptosis by caspase activity. Signaling pathways were evaluated by Western blotting and pharmacological inhibitors. TNF induced classical signs of apoptosis in hGFs, including typical cellular morphology and increased caspase activity. TNF\u2010induced cytotoxicity was entirely caspase\u2010dependent. Pretreatment (4\u201324 h) with EMD dramatically inhibited the activation of initiator and executioner caspases and enhanced hGF survival. Although TNF induced the activation of p38 MAPK, JNK, ERK and PI\u20103K signaling, these pathways were not crucial for EMD protection of hGFs. However, EMD increased the levels of c\u2010FLIP<jats:sub>L<\/jats:sub>, an anti\u2010apoptotic protein located upstream of caspase activation. These data demonstrate, for the first time, that EMD protects hGFs from inflammatory cytokines and, together with our recent reports that EMD stimulates rat and human GF proliferation, could help explain the mechanisms whereby in vivo use of EMD promotes gingival healing. J. Cell. Physiol. 213:750\u2013758. \u00a9 2007 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jcp.21142","type":"journal-article","created":{"date-parts":[[2007,7,2]],"date-time":"2007-07-02T17:48:06Z","timestamp":1183398486000},"page":"750-758","source":"Crossref","is-referenced-by-count":27,"title":["Enamel matrix derivative protects human gingival fibroblasts from TNF\u2010induced apoptosis by inhibiting caspase 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