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Abstract

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-β₁, on gingival proliferation. CsA increased both IL-6 and TGF-β₁ levels. In addition to CsA, an IL-6 or TGF-β₁ 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-β₁ 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.)

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References

Agarwal RK, Sun SH, Su SB, Chan CC, Caspi RR (2002). Pertussis toxin alters the innate and the adaptive immune responses in a pertussis-dependent model of autoimmunity. J Neuroimmunol 129:133–140.

Badache A, Hynes NE (2001). Interleukin 6 inhibits proliferation and, in cooperation with an epidermal growth factor receptor autocrine loop, increases migration of T47D breast cancer cells. Cancer Res 61:383–391.

Buduneli N, Kutukculer N, Aksu G, Atilla G (2001). Evaluation of transforming growth factor-beta 1 level in crevicular fluid of cyclosporin A-treated patients. J Periodontol 72:526–531.

Chae HJ, Chae SW, Chin HY, Bang BG, Cho SB, Han KS, et al. (2001). The p38 mitogen-activated protein kinase pathway regulates interleukin-6 synthesis in response to tumor necrosis factor in osteoblasts. Bone 28:45–53.

Cotrim P, Martelli-Junior H, Graner E, Sauk JJ, Coletta RD (2003). Cyclosporin A induces proliferation in human gingival fibroblasts via induction of transforming growth factor-beta1. J Periodontol 74:1625–1633.

Fan Z, Bau B, Yang H, Aigner T (2004). IL-1beta induction of IL-6 and LIF in normal articular human chondrocytes involves the ERK, p38 and NFkappaB signaling pathways. Cytokine 28:17–24.

Hallmann D, Trumper K, Trusheim H, Ueki K, Kahn CR, Cantley LC, et al. (2003). Altered signaling and cell cycle regulation in embryonal stem cells with a disruption of the gene for phosphoinositide 3-kinase regulatory subunit p85alpha. J Biol Chem 278:5099–5108.

Harkonen M (1999). Medically induced gingival hyperplasia. Mayo Clin Proc 74:742–743.

Linassier C, MacDougall LK, Domin J, Waterfield MD (1997). Molecular cloning and biochemical characterization of a Drosophila phosphatidylinositol-specific phosphoinositide 3-kinase. Biochem J 321(Pt 3):849–856.

10.

McGinn S, Saad S, Poronnik P, Pollock CA (2003). High glucose-mediated effects on endothelial cell proliferation occur via p38 MAP kinase. Am J Physiol Endocrinol Metab 285:E708–E717.

11.

Myrillas TT, Linden GJ, Marley JJ, Irwin CR (1999). Cyclosporin A regulates interleukin-1beta and interleukin-6 expression in gingiva: implications for gingival overgrowth. J Periodontol 70:294–300.

12.

Nakao K, Yoneda K, Osaki T (1995). Enhanced cytokine production and collagen synthesis of gingival fibroblasts from patients with denture fibromatosis. J Dent Res 74:1072–1078.

13.

Park JI, Lee MG, Cho K, Park BJ, Chae KS, Byun DS, et al. (2003). Transforming growth factor-beta1 activates interleukin-6 expression in prostate cancer cells through the synergistic collaboration of the Smad2, p38-NF-kappaB, JNK, and Ras signaling pathways. Oncogene 22:4314–4332.

14.

Ruhl S, Hamberger S, Betz R, Sukkar T, Schmalz G, Seymour RA, et al. (2004). Salivary proteins and cytokines in drug-induced gingival overgrowth. J Dent Res 83:322–326.

15.

Valverde AM, Arribas M, Mur C, Navarro P, Pons S, Cassard-Doulcier AM, et al. (2003). Insulin-induced up-regulated uncoupling protein-1 expression is mediated by insulin receptor substrate 1 through the phosphatidylinositol 3-kinase/Akt signaling pathway in fetal brown adipocytes. J Biol Chem 278:10221–10231.

16.

Voulgari PV, Drosos AA (2002). Gingival hyperplasia associated with cyclosporin A (case report). J Rheumatol 29:2466.

17.

Wahl SM (1985). The role of lymphokines and monokines in fibrosis. Ann NY Acad Sci 460:224–231.

18.

Wang PL, Ohura K, Fujii T, Oido-Mori M, Kowashi Y, Kikuchi M, et al. (2003). DNA microarray analysis of human gingival fibroblasts from healthy and inflammatory gingival tissues. Biochem Biophys Res Commun 305:970–973.

19.

Zhao M, Schmitz AA, Qin Y, Di Cristofano A, Pandolfi PP, Van Aelst L (2001). Phosphoinositide 3-kinase-dependent membrane recruitment of p62(dok) is essential for its negative effect on mitogen-activated protein (MAP) kinase activation. J Exp Med 194:265–274.

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Mechanism of Cyclosporine-induced Overgrowth in Gingiva

Abstract

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