The Role of Interleukin-8 in Cyclosporin A-Induced Gingival Overgrowth

INTRODUCTION: Cyclosporin-A (CsA) has potent immunosuppressant properties derived from its ability to differentially regulate gene expression in activated T cells. CsA downstream targets and network are tissue specific. Differential gene expression, a hallmark of CsA activity, underlies its tissue specific side effects in the kidney, heart and gingiva. CsA differentially alters gene expression in the chemokine-ligand (CXCL)–chemokine-receptor (CXCR) axis, promoting growth and proliferation in various cell types, and activating MAPK-ERK signaling. We hypothesize that CsA induced differential expression of IL-8 (CXCL8) and its receptor, CXCR1, are etiologically important for CsA induced gingival overgrowth (CsAGO). OBJECTIVE: To identify differentially expressed genes in the CXCL-CXCR axis that may drive CsAGO. MATERIALS AND METHODS: Gingival biopsies were taken from 14 renal transplant patients treated with CsA for a minimum of 6 months, and 3 healthy control subjects. Total RNA was extracted using Trizol. Three groups included: controls (n=3), individuals on CsA without GO (n=3), and individuals on CsA with GO (n=11). Assessments of clinical and radiographic parameters were made of the full dentition excluding third molars. Gene expression was determined using the CodeLinkTM Whole Human Genome Gene arrays. Relative expression, integrated gene ontology and pathway analysis was evaluated using the Geospiza Genesifter software package (PerkinElmer) and STRING 9.0. RESULTS: Analysis of cytokine and chemokine ligand and receptors identified more than 50 differentially expressed genes, and CsA treatment was associated with significant increase in expression of IL-8, while CsAGO was associated with a significant increase in CXCR1. SUMMARY AND CONCLUSIONS: CsA drives increased expression levels of IL-8 in human gingival tissues, and CXCR1 is upregulated in CsA GO tissues. Increased IL-8/CXCR1 expression has been reported to drive recruitment and differentiation of pro-fibrotic cells capable of producing an increase in collagen and ECM components in fibrotic diseases of other tissues. Hereditary forms of gingival overgrowth associated with SOS1 and RAS mutations demonstrate up-regulation in MAPK-ERK signaling, and IL-8/CXCR1 can drive a similar pathway. This is the first reported data in the dental literature relating these two fields, and may provide an etiologic mechanism that contributes to CsA-GO in susceptible patients.