Dysregulated Sonic hedgehog signaling and medulloblastoma consequent to IFN-alpha-stimulated STAT2-independent production of IFN-gamma in the brain.
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.
Wang
Jianping
J
The Scripps Research Institute, SP315, 10550 N. Torrey Pines Road, La Jolla, California 92037, USA.
Pham-Mitchell
Ngan
N
Schindler
Christian
C
Campbell
Iain L
IL
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D017252:CD3 Complex / Q000096:biosynthesis; D016543:Central Nervous System Neoplasms / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005838:Genotype; D053823:Hedgehog Proteins; D015151:Immunoblotting; D007150:Immunohistochemistry; D016898:Interferon-alpha / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism*; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D008527:Medulloblastoma / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D012260:Ribonucleases / Q000378:metabolism; D050795:STAT2 Transcription Factor; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism* / Q000502:physiology*
D017252:CD3 Complex; D004268:DNA-Binding Proteins; D053823:Hedgehog Proteins; D016898:Interferon-alpha; D050795:STAT2 Transcription Factor; C494085:Stat2 protein, mouse; D015534:Trans-Activators; D007371:Interferon-gamma; D012260:Ribonucleases; D017493:Leukocyte Common Antigens