Interferon gamma (IFN-γ) is a cytokine predominantly involved in antiproliferative and antiviral responses, immune surveillance, and tumor suppression. However, it has been shown that IFN-γ is also involved in central nervous system development. Here we studied the underlying mechanism for IFN-γ-induced neuronal differentiation using the human neuroblastoma Paju cell line. Our results indicate that IFN-γ treatment led to neurite outgrowth followed by growth arrest in the G1 phase of the cell cycle. IFN-γ induced ERK1/2 phosphorylation and subsequently the transcription factor early gene response 1, which in turn up-regulated p35 expression and increased cyclin-dependent kinase 5 (Cdk5) activity. IFN-γ-induced neurite outgrowth was abolished by the treatment of MEK1/2 kinase inhibitors, such as U0126 and PD98059, which inhibit the ERK1/2 activation and subsequently prevent the up-regulation of p35 expression and Cdk5 activity. In agreement with the role of p35-Cdk5 in neuronal differentiation, small interfering RNA targeting Cdk5 abrogate the IFN-γ-induced neurite outgrowth. Together, these results demonstrate for the first time that IFN-γ-triggered neuronal differentiation mediated through the up-regulation of p35-associated Cdk5 depends on the activation of the ERK1/2 pathway. Therefore, the present study suggests that IFN-γ is not only involved in tumorigenicity but also involved in neurogenesis by regulating cell proliferation and differentiation.
This work was supported in part by a grant from the Canadian Institute of Health Research (to A. S. and C. X. W.) and by funds from the Department of Pathology and Laboratory Medicine, Emory University (to C. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
