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Cyclosporin A Affects Signaling Events Differentially in Human Gingival Fibroblasts

Department of Pathology, Box 357470, University of Washington School of Medicine, Seattle, WA 98195-7470, USA;

^* corresponding author, sampath{at}u.washington.edu

Gingival overgrowth is a common side-effect of the administration of cyclosporin A (CSA), phenytoin, and calcium blockers. To identify the signaling mechanisms possibly involved in the overgrowth, we examined how CSA affects the activities of MAP kinases and transcription factors in human gingival fibroblasts (HGF). The HGF were treated with CSA and TNF- or PDGF. DNA-binding activity of NFAT, NFB, and AP-1 transcription factors was determined by gel shift assay, and JNK, p38, and ERK1 and ERK2 activation was assessed by Western blot analysis of immunoprecipitates. The CSA inhibited NFAT, NFB, and p38 and JNK activities; however, ERK1 and ERK2 were not affected significantly. AP-1 activity increased ~ 4.5-fold. Our results indicate that CSA affects signaling molecules in HGF differently from other cell types, and that a CSA-induced increase in AP-1 activity may affect the expression of fibrogenic molecules in gingiva and promote gingival overgrowth.

KEY WORDS: gingival overgrowth • cyclosporin A • MAP kinases • AP-1 • fibroblasts