Likewise, RAPA was proven to enhance the expression of both COX2 and the microsomal prostaglandin (PG) E synthase-1 and the release of PGE2 and PGD2 in rat microglial cells activated by LPS and poly(I:C) (de Oliveira et al., 2012, 2016). basal conditions and in cells activated with II. Consistently with its known molecular mechanism of action, rapamycin reduced the extent of activation of the so-called ‘mechanistic’ target of rapamycin complex 1 (mTORC1) kinase and the total amount of intracellular proteins. In contrast to rodent cells, rapamycin did not alter human microglial cell viability nor inhibited cell proliferation. Moreover, rapamycin did not exert any significant effect on the morphology of the HMC3 cells. All together these data suggest that the inhibition of mTORC1 in human microglia by rapamycin results in complex immunomodulatory effects, including a significant increase in the expression and release of the pro-inflammatory IL-6. in tuberous sclerosis complex brain lesions (Boer et al., 2008). Histological analysis of the pathological regions confirmed cell-specific activation of mTOR in cortical tubers together with activated microglial cells and disruption of BBB permeability (Boer et al., 2008). Consistently, a downstream target of mTORC1, the phospho-S6 ribosomal protein (p-S6RP) was significantly increased in microglial cells 24 h after traumatic brain injury (Park et al., 2012). It was also shown that the PI3K/AKT/mTOR signaling pathway together with the hypoxia inducible factor-1 (HIF-1) mediated the up-regulation of the inducible nitric oxide (NO) synthase (NOS2) in response to hypoxia, both in Farampator primary rat microglial cultures and in the mouse BV-2 microglial cell line (Lu et al., Farampator 2006). Consistently, we have shown that Farampator mTORC1 activation is increased in rat primary microglial cells in response to different inflammatory stimuli (the bacterial endotoxin lipopolysaccharide LPS, or a mixture of pro-inflammatory cytokines) (Dello Russo et al., 2009) or by the exposure to glioma conditioned medium (Lisi et al., 2014). However, the role of mTOR in the regulation of microglial inflammatory responses is still not completely understood. For example, in our experiments we observed both anti-inflammatory and pro-inflammatory effects in response to RAPA. Namely, the drug reduced NOS2 activity and expression in response to cytokines; increased NOS2 expression, leaving significantly unaffected the enzymatic activity, in LPS-treated microglia; and significantly increased NOS2 expression and activity in glioma activated-microglial cells (Dello Russo et al., 2009; Lisi et al., 2014). On the other hand, the mTOR inhibitor RAD001 tended to reduce the cytosolic level of cyclooxygenase 2 (COX2) in microglial cells activated by pro-inflammatory cytokines, whereas it displayed significantly stimulatory effects on COX2 when administered in resting microglia (Dello Russo et al., 2009). In catalase-exposed BV2 microglial cells, mTOR inhibition reduced both COX2 and NOS2 protein levels without affecting the mRNA steady state levels (Jang et al., 2005). This effect was due to reduced activity of the mTORC1 downstream target, p70S6 kinase (p70S6K), which is a critical regulator of protein translation. In addition, reduction of NOS2 and interleukin 6 (IL-6) mRNA levels together with increased TNFAIP3 autophagic processes were observed in response to 100 nM RAPA in LPS-stimulated BV2 microglial cells (Han et al., 2013). However, the mRNA Farampator level of other inflammatory genes, including IL-12, IFN, IFN, and TNF, was increased by RAPA in this experimental model (Han et al., 2013). Similarly, RAPA was shown to enhance the expression of both COX2 and the microsomal prostaglandin (PG) E synthase-1 and the release of PGE2 and PGD2 in rat microglial cells activated by LPS and poly(I:C).