Dysregulated Sonic hedgehog signaling and medulloblastoma consequent to IFN-alpha-stimulated STAT2-independent production of IFN-gamma in the brain

J Clin Invest. 2003 Aug;112(4):535-43. doi: 10.1172/JCI18637.

Abstract

The type I IFNs (IFN-alpha and IFN-beta), 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-alpha. Surprisingly, GIFN/STAT2-/-, but not GIFN/STAT1-null, transgenic mice, with CNS production of IFN-alpha, died prematurely with medulloblastoma. An immune response also induced in the brain of the GIFN/STAT2-/- mice was associated with IFN-gamma 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-gamma, but not IFN-alpha, 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-alpha 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-gamma.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blotting, Western
  • Brain / metabolism*
  • CD3 Complex / biosynthesis
  • Central Nervous System Neoplasms / metabolism
  • Cerebellum / metabolism
  • DNA-Binding Proteins / metabolism*
  • Genotype
  • Hedgehog Proteins
  • Immunoblotting
  • Immunohistochemistry
  • Interferon-alpha / metabolism*
  • Interferon-gamma / metabolism*
  • Leukocyte Common Antigens / biosynthesis
  • Medulloblastoma / metabolism*
  • Mice
  • Mice, Transgenic
  • Neurons / cytology
  • Neurons / metabolism
  • Ribonucleases / metabolism
  • STAT2 Transcription Factor
  • Signal Transduction
  • Spleen / cytology
  • T-Lymphocytes / metabolism
  • Time Factors
  • Trans-Activators / metabolism*
  • Trans-Activators / physiology*

Substances

  • CD3 Complex
  • DNA-Binding Proteins
  • Hedgehog Proteins
  • Interferon-alpha
  • STAT2 Transcription Factor
  • Stat2 protein, mouse
  • Trans-Activators
  • Interferon-gamma
  • Ribonucleases
  • Leukocyte Common Antigens