title: The mTOR kinase inhibitors polarize glioma-activated microglia to express a M1 phenotype.
abstract: BACKGROUND
  Increased activation of mammalian target of rapamycin (mTOR) is observed in numerous human cancers. Recent studies on the glioma kinome have identified several deregulated pathways that converge and activate mTOR. The available evidence on the role of microglia in CNS cancers would suggest a dual role, a tumoricidal role and -on the contrary- a role favoring tumor growth.
  
  
  METHODS
  In the present paper, we have compared the effects of μM concentrations of rapamycin (RAPA) and its analog, RAD001 (RAD), on activated microglia; the latter was obtained by exposing cells to conditioned medium harvested either from inflammatory activated glioma cells (LI-CM) or from glioma cells kept under basal conditions (C-CM).
  
  
  RESULTS
  Here we show that the inhibition of mTOR polarizes glioma-activated microglial cells towards the M1 phenotype, with cytotoxic activities, preventing the induction of the M2 status that promotes tumor growth. In fact RAPA and RAD significantly increased iNOS expression and activity, while on the same time significantly reducing IL-10 gene expression induced by C-CM, thus suggesting that the drugs prevent the acquisition of a M2 phenotype in response to glioma factors promoting a classic M1 activation. Similar results were obtained using the conditioned media obtained after glioma stimulation with LPS-IFNγ (LI-CM), which was found to induce a mixture of M1 and M2a/b polarization phenotypes. In these conditions, the inhibition of mTOR led to a significant up-regulation of iNOS, and in parallel to the down-regulation of both ARG and IL-10 gene expression.
  
  
  CONCLUSIONS
  These data suggest that mTOR inhibition may prevent glioma induced M2 polarization of microglial cells and increase their cytotoxic potential, possibly resulting in antitumor actions.
authors: Lucia
authors: L
authors: Lisi
authors: Emilia
authors: E
authors: Laudati
authors: Institute of Pharmacology, Catholic University Medical School, L,go F Vito 1, 00168 Rome, Italy. pnavarra@rm.unicatt.it.
authors: Pierluigi
authors: P
authors: Navarra
authors: Cinzia
authors: C
authors: Dello Russo
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001119:Arginase / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005910:Glioma / Q000473:pathology*; D016898:Interferon-alpha / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D009457:Neuroglia / Q000187:drug effects*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors
chemical_list: D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D016898:Interferon-alpha; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D001119:Arginase; C542908:arginase I, rat; D001973:Bromodeoxyuridine