Prior Chronic in Vivo Glucocorticoid Excess Leads to an Anabolic Phenotype and an Extension of Cellular Life Span of Skin Fibroblasts in Vitro

摘要

Intense stress can be detrimental for tissue homeostasis and accelerates aging. On the other hand, repeated mild stresses can have beneficial and even life-prolonging effects. Hypersecretion of glucocorti-coids (GCs) represents the major hormonal response to stress. However, besides its life-sustaining role, GC excess can promote a "catabolic" phe-notype. Accordingly, we have studied the effect of long-lasting exposure to high GC levels in vivo on several parameters of tissue homeostasis, as well as cellular senescence, in cells removed from the high-GC milieu in vivo and then cultured in vitro. To this end, we have used human skin fibroblasts from (a) Cushing's syndrome patients that are characterized by chronic endogenous GC excess and (b) patients treated with exogenous GC administration. Interestingly, when Cushing's syndrome fibroblasts were cultured in vitro under standard conditions they express an "anabolic" phenotype, i.e., they restore their ability for collagen synthesis, secrete reduced levels of metalloproteases, and have an increased proliferative capacity and contractility. Furthermore, these cells exhibit a significant extension of their proliferative life span, while they respond better to exogenous stress by producing significantly higher levels of heat-shock protein-70 (HSP70). In addition, preliminary results with fibroblasts from patients subjected to chronic exogenous GC administration indicate that they express a similar behavior in vitro, at least with regard to the restoration of collagen expression. These data suggest that prior exposure to elevated GC concentrations is not associated with persisting adverse effects on fibroblasts and may also have a beneficial outcome in some aspects of cell physiology, including longevity in vitro.