Intracellular network of phosphatidylinositol 3-kinase, mammalian target of the rapamycin/70 kDa ribosomal S6 kinase 1, and mitogen-activated protein kinases pathways for regulating mycobacteria-induced IL-23 expression in human macrophages

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Abstract
We previously demonstrated that Mycobacterium tuberculosis (M. tbc)‐induced interleukin (IL)‐12 expression is negatively regulated by the phosphatidylinositol 3‐kinase (PI3K) and extracellular signal‐regulated kinase (ERK) 1/2 pathways in human monocyte‐derived macrophages (MDMs). To extend these studies, we examined the nature of the involvement of toll‐like receptors (TLRs) and intracellular signalling pathways downstream from PI3K in M. tbc‐induced IL‐23 expression in human MDMs. M. tbc‐induced Akt activation and IL‐23 expression were essentially dependent on TLR2. Blockade of the mammalian targets of rapamycin (mTOR)/70 kDa ribosomal S6 kinase 1 (S6K1) pathway by the specific inhibitor rapamycin greatly enhanced M. tbc‐induced IL‐12/IL‐23 p40 (p40) and IL‐23 p19 (p19) mRNA and IL‐23 protein expression. In sharp contrast, p38 mitogen‐activated protein kinase (MAPK) inhibition abrogated the p40 and p19 mRNA and IL‐23 protein expression induced by M. tbc. Furthermore, the inhibition of PI3K‐Akt, but not ERK 1/2 pathway, attenuated M. tbc‐induced S6K1 phosphorylation, whereas PI3K inhibition enhanced p38 phosphorylation and apoptosis signal‐regulating kinase 1 activity during exposure to M. tbc. Although the negative or positive regulation of IL‐23 was not reversed by neutralization of IL‐10, it was significantly modulated by blocking TLR2. Collectively, these findings provide new insight into the homeostatic mechanism controlling type 1 immune responses during mycobacterial infection involving the intracellular network of PI3K, S6K1, ERK 1/2 and p38 MAPK pathways in a TLR2‐dependent manner.

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