Background and Objectives PPAR-gamma is an essential transcription factor that apart from participating in the regulation of genes associated with lipogenesis, it exerts significant anti-inflammatory actions. PPAR-gamma has been implicated in the pathogenesis of human autoimmune diseases that are characterised by the inflammatory damage of epithelial cells. More specifically, dramatically reduced expression of PPAR-gamma has been shown in the epithelial cells of the intestinal tract and of the biliary tree of patients with ulcerative colitis and primary biliary cirrhosis, respectively. Primary Sjögren’s syndrome (SS or autoimmune epithelitis) is characterised by chronic inflammatory lesions mainly affecting epithelial tissues and is associated with systemic autoimmune responses and the chronic intrinsic activation of salivary gland epithelial cells (SGEC). Thus, SGEC are probably both the target and the inducer of inflammatory responses. In this context, we aimed to investigate the levels of constitutive expression of PPAR-gamma in cultured non-neoplastic SGEC lines from SS patients and non-SS controls, as well as the patterns of PPAR-gamma expression following cellular activation.
Materials and Methods To examine the levels of mRNA expression of PPAR-g, total RNA was isolated from long-term cultured non-neoplastic SGEC and from peripheral blood mononuclear cells (PBMCs) of 18 SS patients and 11 non-SS disease controls. The expression of PPAR-gamma was studied by Real-time PCR with primers specific for PPAR-gamma and the reporter gene HPRT1 and analysed by the ddCt method. To evaluate the effect of epithelial activation in the expression of PPAR-g, SGEC from non-SS controls were stimulated with specific ligands of TLR-3 (Polyinosinic-polycytidylic acid, PolyI:C, 5 mg/ml), TLR-4 (lipopolysaccharide, LPS, 1 mg/ml) receptor and with the cytokine IFN-gamma (500 U/ml).
Results PPAR-gamma mRNA expression was significantly reduced in the SGEC from patients with SS, compared to controls (p = 0.0001). In contrast, no difference was found in PPAR-gamma expression in PBMCs between patients and controls. The activation of cultured SGEC by stimulation with PolyI:C, LPS and IFN-g resulted in a significant down-regulation of PPAR-gamma mRNA expression (in all cases; by ≈80% at 12 hours, p = 0.0001).
Conclusions Our findings indicate that the expression of PPAR-gamma in human epithelial cells is significantly reduced following activation via TLRs and the Th1 cytokine INF-gamma. Furthermore, the present study demonstrates for the first time the significantly reduced expression of PPAR-gamma in the SGEC of SS patients. This finding likely owes to the chronic intrinsic activation, which characterises the epithelia of SS patients.
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