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Astrocytic Regulation of Human Monocytic/Microglial Activation¹

Alex M. Kostianovsky^*, Lisa M. Maier^*, Richard C. Anderson, Jeffrey N. Bruce and David E. Anderson^2,*

^* Department of Neurology, Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115; and The Gabriele Bartoli Brain Tumor Research Laboratory, Department of Neurological Surgery, The Neurological Institute, Columbia University College of Physicians and Surgeons, New York City, NY 10032

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by an American Cancer Society Research Scholar Grant (to D.E.A.).

² Address correspondence and reprint requests to Dr. David E. Anderson, Department of Neurology, Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, NRB 641, Boston, MA 02115. E-mail address: danderson{at}rics.bwh.harvard.edu

³ Abbreviations used in this paper: DC, dendritic cell; GBM, glioblastoma multiforme; NHA, nontransformed human astrocyte; MFI, mean fluorescence intensity.

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