Dysregulated Sonic hedgehog signaling and medulloblastoma consequent to IFN-α–stimulated STAT2-independent production of IFN-γ in the brain

Abstract

The type I IFNs (IFN-α and IFN-β), which are crucial in antiviral defense and immune regulation, signal via the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway with activation of STAT1 and STAT2. Here, the function of STAT2 was studied in transgenic mice (termed GIFN/STAT2 -/-) with CNS production of IFN-α. Surprisingly, GIFN/STAT2 -/-, but not GIFN/STAT1-null, transgenic mice, with CNS production of IFN-α, died prematurely with medulloblastoma. An immune response also induced in the brain of the GIFN/STAT2 -/-mice was associated with IFN-γ gene expression by CD3 + T cells and the activation of the STAT1, STAT3, STAT4, and STAT5 molecules. Expression of the Sonic hedgehog (Shh) and the downstream transcriptional factor Gli-1 genes, implicated in the pathogenesis of medulloblastoma, was found to be significantly increased and cotranscribed in cerebellar granule neurons of the GIFN/STAT2 -/-mice. IFN-γ, but not IFN-α, induced STAT1-dependent expression of the Shh gene in cultured cerebellar granule neurons. Thus, there is an unexpected and extraordinarily adverse biological potency of IFN-α in the CNS when the primary signal transduction molecule STAT2 is absent. Moreover, a hitherto unknown role is indicated for the immune system in the pathogenesis of developmental disorders and tumorigenesis of the CNS via dysregulated Shh signaling mediated by IFN-γ.

The Type I Interferon-α Mediates a More Severe Neurological Disease in the Absence of the Canonical Signaling Molecule Interferon Regulatory Factor 9

“…Although the cellular source of IFN-␥ gene expression in the CNS of the GIFNxIRF9 KO mice was not identified, IFN-␣ can induce IFN-␥ gene expression in murine T cells lacking either STAT1 or STAT2 via the activation of STAT4 (Nguyen et al, 2002;Wang et al, 2003). The presence of IFN-␥ mRNA in the brain of the GIFNxIRF9 KO mice is therefore likely to have been induced in infiltrating T cells that were responding to IFN-␣.…”

Systemic interferon-α regulates interferon-stimulated genes in the central nervous system

“…The RNase protection assay (RPA) probe for dsRNA-dependent protein kinase R (PKR), USP18, STAT1, ISG15, GBP3, IP-10, IFN-a1, IFN-b and IFN-g were prepared and the RPA was performed as described previously. 25,26 Briefly, 32 P-UTP (Amersham Biosciences, Piscataway, NJ, USA) labeled ribosomal antisense RNA probes were hybridized with the RNA extracted from dissected tissues. After RNase treatment, undigested probes were extracted, precipitated and separated on 5% acrylamide sequence gel.…”

“…For quantification, densitometric analysis of each band was performed on scanned autoradiographs using NIH Image 1.62 software. 26 In situ hybridization and immunocytochemistry Following perfusion with 4% paraformaldehyde in 0.1 M phosphate buffer, brains were removed and fixed overnight in ice-cold 4% paraformaldehyde in phosphate buffer (pH 7.4). Paraffin-embedded sagittal sections (8 mm) were prepared for in situ hybridization.…”

Attenuation of Experimental Autoimmune Encephalomyelitis and Nonimmune Demyelination by IFN-β plus Vitamin B12: Treatment to Modify Notch-1/Sonic Hedgehog Balance

“…Shh has been reported to be regulated via signal transduction system in mouse brain (42), and methylation of STAT-1 regulates gene expression (17). To determine whether STAT-1 was affected by the various treatments, we measured STAT-1 in brain homogenates (Fig.…”