A direct cross-talk between interferon-gamma and sonic hedgehog signaling that leads to the proliferation of neuronal precursor cells.
Interferon-gamma (IFN-gamma) is a pleiotropic cytokine that is critical for innate and adaptive immunity. Recent evidence suggests a connection between IFN-gamma signaling and the sonic hedgehog (Shh) pathway in the developing brain with CNS-targeted expression of IFN-gamma transgene in mice. To determine the relationship between these distinct pathways, we have found that IFN-gamma induces a rapid Shh transcription in cultured primary granular neuron precursor (GNP) cells. The transcriptional induction of Shh by IFN-gamma is resistant to protein synthesis inhibition. Chromatin immunoprecipitation (ChIP) analysis reveals a direct binding of signal transducer and activator of transcription (STAT) 1 to the Shh promoter. Functional analyses, including dual immunofluorescent labeling with 5-bromodeoxyuridine (BrdU) incorporation indicate that IFN-gamma treatment leads to significant GNP proliferation. This mitogenic effect of IFN-gamma is blocked by inhibition of Shh signaling. Therefore, Shh is an IFN-gamma target gene and is responsible for IFN-gamma-induced GNP proliferation. This previously unrecognized cross-talk between IFN-gamma and Shh highlights a potential importance of this immune mediator in the pathogenesis of human developmental and psychiatric disorders.
Department of Pharmacology and Toxicology, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
Li
L
Sun
Zhanzhuang
Z
Tian
Jianping
J
Wang
D000818:Animals; D000963:Antimetabolites; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D049109:Cell Proliferation; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004396:Coloring Agents; D053823:Hedgehog Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008938:Mitosis / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D023282:Nuclease Protection Assays; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D020239:Receptor Cross-Talk / Q000502:physiology*; D012260:Ribonucleases / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013778:Tetrazolium Salts; D013844:Thiazoles
D000963:Antimetabolites; D004396:Coloring Agents; D053823:Hedgehog Proteins; D050794:STAT1 Transcription Factor; C465570:Shh protein, mouse; D013778:Tetrazolium Salts; D013844:Thiazoles; D012313:RNA; D007371:Interferon-gamma; D012260:Ribonucleases; C022616:thiazolyl blue; D001973:Bromodeoxyuridine