title: Aberrant expression of interleukin-1β and inflammasome activation in human malignant gliomas.
abstract: OBJECTIVE
  Glioblastoma is the most frequent and malignant form of primary brain tumor with grave prognosis. Mounting evidence supports that chronic inflammation (such as chronic overactivation of IL-1 system) is a crucial event in carcinogenesis and tumor progression. IL-1 also is an important cytokine with species-dependent regulations and roles in CNS cell activation. While much attention is paid to specific anti-tumor immunity, little is known about the role of chronic inflammation/innate immunity in glioma pathogenesis. In this study, we examined whether human astrocytic cells (including malignant gliomas) can produce IL-1 and its role in glioma progression.
  
  
  METHODS
  We used a combination of cell culture, real-time PCR, ELISA, western blot, immunocytochemistry, siRNA and plasmid transfection, micro-RNA analysis, angiogenesis (tube formation) assay, and neurotoxicity assay.
  
  
  RESULTS
  Glioblastoma cells produced large quantities of IL-1 when activated, resembling macrophages/microglia. The activation signal was provided by IL-1 but not the pathogenic components LPS or poly IC. Glioblastoma cells were highly sensitive to IL-1 stimulation, suggesting its relevance in vivo. In human astrocytes, IL-1β mRNA was not translated to protein. Plasmid transfection also failed to produce IL-1 protein, suggesting active repression. Suppression of microRNAs that can target IL-1α/β did not induce IL-1 protein. Glioblastoma IL-1β processing occurred by the NLRP3 inflammasome, and ATP and nigericin increased IL-1β processing by upregulating NLRP3 expression, similar to macrophages. RNAi of annexin A2, a protein strongly implicated in glioma progression, prevented IL-1 induction, demonstrating its new role in innate immune activation. IL-1 also activated Stat3, a transcription factor crucial in glioma progression. IL-1 activated glioblastoma-conditioned media enhanced angiogenesis and neurotoxicity.
  
  
  CONCLUSIONS
  Our results demonstrate unique, species-dependent immune activation mechanisms involving human astrocytes and astrogliomas. Specifically, the ability to produce IL-1 by glioblastoma cells may confer them a mesenchymal phenotype including increased migratory capacity, unique gene signature and proinflammatory signaling.
authors: Department of Pathology (Neuropathology), Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, United States of America.
authors: Leonid
authors: L
authors: Tarassishin
authors: Department of Neurosurgery, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, United States of America.
authors: Diana
authors: D
authors: Casper
authors: Department of Pathology (Neuropathology), Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, United States of America.
authors: Sunhee C
authors: SC
authors: Lee
mesh_terms: D000368:Aged; D001921:Brain / Q000276:immunology / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002648:Child; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D006801:Humans; D058847:Inflammasomes / Q000276:immunology*; D053583:Interleukin-1beta / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; D012333:RNA, Messenger