کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
3069593 | 1580698 | 2011 | 9 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: STAT3 inhibitors attenuate interferon-γ-induced neurotoxicity and inflammatory molecule production by human astrocytes STAT3 inhibitors attenuate interferon-γ-induced neurotoxicity and inflammatory molecule production by human astrocytes](/preview/png/3069593.png)
Activation of signal transducer and activator of transcription (STAT) 3 is observable in reactive astrocytes under certain neuropathological conditions. Interferon (IFN)-γ is shown to activate STAT3 in cultured rodent astrocytes. Here we investigated the effects of inhibiting STAT3 signaling on IFNγ-activated human astrocytes since we have recently demonstrated that human astrocytes become neurotoxic when stimulated by IFNγ. We found that 5′-deoxy-5′-(methylthio)adenosine (MTA) (300 μM), S3I-201 (10 μM), STAT3 inhibitor VII (3 μM) and JAK-inhibitor I (0.3 μM) had anti-neurotoxic effects on IFN-γ (50 U/ml)-activated astrocytes and U373-MG astrocytoma cells. Another inhibitor, AG490 (30 μM) had no significant effect. The active inhibitors also attenuated IFN-γ-induced phosphorylation of Tyr705-STAT3 and astrocytic expression of intercellular adhesion molecule-1 (ICAM-1). They also decreased astrocytic production of IFN-γ-inducible T cell α chemoattractant (I-TAC). AG490, which did not affect the Tyr705-STAT3 phosphorylation or ICAM-1 expression, nevertheless reduced the I-TAC secretion. Because these results indicate that pharmacological inhibition of STAT3 signaling correlates with reduced astrocytic neurotoxicity and ICAM-1 expression, but not that of I-TAC secretion, we consider that STAT3 activation mediates, at least in part, the IFN-γ-induced neurotoxicity and ICAM-1 expression by human astrocytes.
Research Highlights
► 5′-deoxy-5′-(methylthio)adenosine, S3I-201, STAT3 inhibitor VII and JAK-inhibitor I inhibit IFN-γ-induced Tyr705-STAT3 phosphorylation in human astrocytes.
► STAT 3 inhibitors attenuate IFN-γ-induced neurotoxicity of human astrocytes.
► STAT 3 inhibitors suppress IFN-γ-induced ICAM-1 expression by human astrocytes.
Journal: Neurobiology of Disease - Volume 41, Issue 2, February 2011, Pages 299–307