地塞米松和他克莫司对HaCaT细胞糖皮质激素受体和热休克蛋白90表达调节-皮肤病与性病学专业论文.docx

第三军医大学博士学位论文 第三军医大学博士学位论文 PAGE PAGE 4 Effects of dexamethasone and tacrolimus on glucocorticoid receptor and heat shock protein 90 expressions in human HaCaT cells in vitro Abstract Background Topical glucocorticoid (GC) therapy is mainly a routine therapeutic modality for the treatment of inflammatory dermatoses. A low response or missing response to topical GC therapy, which is called tolerance or resistance to GC, often occurs during the treatment. The actions of GCs are mediated by the intracellular receptor, the glucocorticoid receptor (GR). Evidence obtained from some laboratories indicates that the decreased expression or affinity of GRα can alter the sensitivity of cells to GCs and the increased expression of GRβ may be associated with the ineffectiveness of GCs in the treatment of different diseases. Changes in the expression of heat shock protein 90 (HSP90), molecular chaperone of GR, lead to disequilibrium in the ratio of HSP90 and GR, which could cause attenuation of GC sensitivity. Down-regulation of GRα or up-regulation of GRβ induced by GC could partially account for tolerance or resistance to GC. In order to postpone or decrease occurrence of these phenomena, dermatologists usually apply GCs and non-GC anti-inflammatory agents alternately, which just was a kind of empirical prescription without experimental evidence. Tacrolimus ointment has shown remarkable efficacy in the treatment of inflammatory dermatoses. Some studies in vitro found that tacrolimus might induce activation of GRα in Hela cells or COS-7 cells. Down-regulation of GRα or up-regulation of GRβ induced by GC in cells suggests the necessity of controlling the duration of topical GC treatment. However, the subsequent changes of GR expression after withdrawal of GC remain unknown. Effects of tacrolimus, which appeared to potentially correlate with GC action, or tacrolimus in combination of GC, on expression of GR are still unclear. Dermal inflammation often involves different types of