The Role of Chemokines in Cyclosporine Induced Gingival Overgrowth

This study investigated the role of chemokines in Cyclosporine (CsA) induced gingival overgrowth (GO). 14 patients with renal transplants undergoing CsA treatment and 3 healthy subjects were selected for this study from a larger subpopulation. 11 individuals on CsA treatment experienced GO, while 3 subjects did not have clinical evidence of GO. Gingival biopsy samples were taken for all individuals in the three groups (control, healthy n=3; CsA NO GO n=3; CsA GO n=11). RNA was extracted from the biopsy samples and gene array analyses for differential expression were performed. CsA treatment was associated with increased chemokine expression globally; this was more evident in the CsA GO group. Chemokines reported in the literature to be pro-fibrotic (CCL2, CCL3, CCL5) were significantly increased in the CsA GO group. Additionally, the chemokine ligand-receptor axis of CXCL8/CXCR1 and CXCL16/CXCR6 were notably increased in the CsA GO group alone. These ligand-receptor interactions are increased in fibrosis of the liver and kidney. CsA NO GO subjects had increased chemokine ligand production without the paired receptor. This may represent a protected immune response, resulting in no GO in certain individuals. Investigation of upstream toll-like receptor (TLR) signaling revealed an increase in TLR1, TLR2, and TLR4, which may drive chemokine potentiation in addition to CsA tissue specific effects. The process of CsA GO involves active fibroblast transformation from pericytes, fibrocytes, or the epithelial mesenchymal transition. Chemokines are intimately involved in the aforementioned cells and events. Therefore, CsA treatment may alter chemokine levels and function through some or all of these pathways to produce a GO response in certain individuals.