Astrocytic regulation of human monocytic/microglial activation.
Recent reports have described reduced immunological responsiveness and stimulatory capacity among monocytes/microglia that infiltrate malignant human gliomas. Herein, we demonstrate that culture of ex vivo human monocytes or primary human microglia with tumor cells isolated from glioblastoma multiforme (GBM) specimens renders them tolerogenic, capable of suppressing the function of ex vivo monocytes in the absence of tumor cells or their soluble factors. We demonstrate that the tolerance induced in monocytes/microglia by GBM tumor cells is not associated with interference with the signaling cascade associated with TLR- or CD40-induced monocyte activation. Rather, these tumor cells appear to up-regulate pathways that antagonize positive signaling pathways, including but not limited to STAT3 and STAT5. Finally, we demonstrate that the tolerogenic properties of GBM tumor cells amplify properties inherent to nontransformed astrocytes. Future studies that identify all of the molecular mechanisms by which astrocytes and malignant gliomas suppress monocyte/microglial function will have dual therapeutic benefits: suppressing these pathways may benefit patients with astrocytic tumors, while enhancing them may benefit patients with autoimmune processes within the CNS, such as multiple sclerosis.
Kostianovsky
Alex M
AM
Department of Neurology, Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Maier
Lisa M
LM
Anderson
Richard C
RC
Bruce
Jeffrey N
JN
Anderson
David E
DE
D001253:Astrocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019013:CD40 Antigens / Q000276:immunology; D005910:Glioma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D006801:Humans; D017628:Microglia / Q000276:immunology* / Q000473:pathology; D009000:Monocytes / Q000276:immunology* / Q000473:pathology; D009103:Multiple Sclerosis / Q000276:immunology / Q000473:pathology / Q000628:therapy; D050796:STAT3 Transcription Factor / Q000276:immunology; D050799:STAT5 Transcription Factor / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology; D014407:Tumor Cells, Cultured
D019013:CD40 Antigens; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D051193:Toll-Like Receptors