Mechanism of cyclosporine-induced overgrowth in gingiva

Cyclosporine A (CsA) is a widely used immunosuppressant but with significant side-effects, such as gingival overgrowth. This study investigates how CsA induces gingival proliferation and shows the effects of the CsA-associated signaling messengers, IL-6 and TGF-beta(1), on gingival proliferation. CsA increased both IL-6 and TGF-beta(1) levels. In addition to CsA, an IL-6 or TGF-beta(1) treatment also induced gingival fibroblast proliferation. Inhibiting the cytokine resulted in the suppression of CsA-induced proliferation. MAPKs and PI3K are known to be involved in cell proliferation. Therefore, the effect of CsA on the kinase activities was examined. The results showed that both p38 MAPK and PI3K are essential for gingival fibroblast proliferation. TGF-beta(1) and IL-6 and their associated signaling transduction may be novel bona fide molecular targets for the prevention of gingival overgrowth in CsA-treated patients. (Abbreviations: MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3-kinase.)