Interleukin-1beta enhances the angiotensin-induced expression of plasminogen activator inhibitor-1 through angiotensin receptor upregulation in human astrocytes.

摘要

Plasminogen activator inhibitor-1 (PAI-1) regulates not only fibrinolysis but extracellular matrix remodeling, and angiotensin II is known to play an important role in controlling the expression of PAI-1 in astrocytes. We have studied the effect of interleukin-1beta (IL-1beta), one of major cytokines also active in the nervous system, on the angiotensin II-induced expression of PAI-1 in human astrocytes. Cultures of normal human astrocytes were stimulated with IL-1beta and angiotensin II, and the expression of mRNAs for angiotensin II type 1 receptor (AT1) and PAI-1 was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) or real-time quantitative PCR. PAI-1 protein in astrocyte-conditioned medium was measured by enzyme-linked immunosorbent assay (ELISA). IL-1beta enhanced the expression of AT1 in astrocytes in time- and concentration-dependent manners. After 24-h stimulation, 10 ng/ml IL-1beta and 10 nM angiotensin II increased the levels of PAI-1 protein in astrocyte-conditioned medium by 1.9-fold and 1.8-fold of the basal value, respectively. There was no synergistic effect when the cells were stimulated simultaneously with IL-1beta and angiotensin II. When the cells were stimulated, with angiotensin II, 16 h after the stimulation with IL-1beta, the production of PAI-1 was enhanced by 1.4-fold as compared to the cells stimulated only with IL-1beta. CV-11794, an AT1 antagonist, inhibited the enhanced PAI-1 production in response to angiotensin II. We conclude that IL-1beta increases angiotensin II-induced PAI-1 secretion by astrocytes through the induction of AT1, and the enhanced secretion of PAI-1 may modulate functions of plasminogen activators in the nervous system.