PMID- 25051975 OWN - NLM STAT- MEDLINE DCOM- 20150330 LR - 20211203 IS - 1742-2094 (Electronic) IS - 1742-2094 (Linking) VI - 11 DP - 2014 Jul 23 TI - The mTOR kinase inhibitors polarize glioma-activated microglia to express a M1 phenotype. PG - 125 LID - 10.1186/1742-2094-11-125 [doi] AB - 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 muM 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-IFNgamma (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. FAU - Lisi, Lucia AU - Lisi L FAU - Laudati, Emilia AU - Laudati E FAU - Navarra, Pierluigi AU - Navarra P AD - Institute of Pharmacology, Catholic University Medical School, L,go F Vito 1, 00168 Rome, Italy. pnavarra@rm.unicatt.it. FAU - Dello Russo, Cinzia AU - Dello Russo C LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140723 PL - England TA - J Neuroinflammation JT - Journal of neuroinflammation JID - 101222974 RN - 0 (Culture Media, Conditioned) RN - 0 (Enzyme Inhibitors) RN - 0 (Interferon-alpha) RN - 0 (Lipopolysaccharides) RN - 0 (RNA, Messenger) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type II) RN - EC 1.14.13.39 (Nos2 protein, mouse) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.5.3.1 (Arginase) RN - EC 3.5.3.1 (arginase I, rat) RN - G34N38R2N1 (Bromodeoxyuridine) SB - IM MH - Analysis of Variance MH - Animals MH - Arginase/metabolism MH - Bromodeoxyuridine/metabolism MH - Cell Proliferation/drug effects MH - Cells, Cultured MH - Cerebral Cortex/cytology MH - Culture Media, Conditioned/pharmacology MH - Enzyme Inhibitors/*pharmacology MH - Glioma/*pathology MH - Interferon-alpha/metabolism MH - Lipopolysaccharides/pharmacology MH - Neuroglia/*drug effects MH - Nitric Oxide Synthase Type II/metabolism MH - Phosphorylation/drug effects MH - RNA, Messenger/metabolism MH - Rats MH - TOR Serine-Threonine Kinases/*metabolism MH - Time Factors PMC - PMC4128534 EDAT- 2014/07/24 06:00 MHDA- 2015/03/31 06:00 PMCR- 2014/07/23 CRDT- 2014/07/24 06:00 PHST- 2014/04/29 00:00 [received] PHST- 2014/07/14 00:00 [accepted] PHST- 2014/07/24 06:00 [entrez] PHST- 2014/07/24 06:00 [pubmed] PHST- 2015/03/31 06:00 [medline] PHST- 2014/07/23 00:00 [pmc-release] AID - 1742-2094-11-125 [pii] AID - 10.1186/1742-2094-11-125 [doi] PST - epublish SO - J Neuroinflammation. 2014 Jul 23;11:125. doi: 10.1186/1742-2094-11-125.