Aberrant expression of interleukin-1β and inflammasome activation in human malignant gliomas

Leonid Tarassishin, Diana Casper, Sunhee C. Lee

Research output: Contribution to journalArticle

42 Citations (Scopus)

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 glioblastomaconditioned 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.

Original languageEnglish (US)
Article numbere103432
JournalPLoS One
Volume9
Issue number7
DOIs
StatePublished - Jul 23 2014

Fingerprint

Inflammasomes
interleukin-1
Interleukin-1
Glioma
Chemical activation
Glioblastoma
Tumors
neurotoxicity
Macrophages
astrocytes
transfection
angiogenesis
MicroRNAs
microRNA
Astrocytes
neoplasms
Transfection
cells
Assays
plasmids

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Aberrant expression of interleukin-1β and inflammasome activation in human malignant gliomas. / Tarassishin, Leonid; Casper, Diana; Lee, Sunhee C.

In: PLoS One, Vol. 9, No. 7, e103432, 23.07.2014.

Research output: Contribution to journalArticle

Tarassishin, Leonid ; Casper, Diana ; Lee, Sunhee C. / Aberrant expression of interleukin-1β and inflammasome activation in human malignant gliomas. In: PLoS One. 2014 ; Vol. 9, No. 7.
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