STAT3 inhibitors attenuate interferon-γ-induced neurotoxicity and inflammatory molecule production by human astrocytes

Neurobiology of Disease

Andis Klegeris¹  Sadayuki Hashioka²  Patrick L. McGeer²  Hong Qing² 

[1] Department of Biology, I.K. Barber School of Arts and Sciences, The University of British Columbia Okanagan, 3333 University Way, Kelowna, BC, Canada V1V 1V7;Kinsmen Laboratory of Neurological Research, Department of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, Canada V6T 2A1;

关键词: STAT3 signaling;    Astrocytes;    Interferon-γ;    Neurotoxicity;    ICAM-1;    I-TAC;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown