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.
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.
Yang
Chul-Su
CS
Department of Microbiology, College of Medicine, Chungnam National University, Daejeon 301-747, South Korea.
Song
Chang-Hwa
CH
Lee
Ji-Sook
JS
Jung
Saet-Byel
SB
Oh
Jae-Hee
JH
Park
Jongsun
J
Kim
Hwa-Jung
HJ
Park
Jeong-Kyu
JK
Paik
Tae-Hyun
TH
Jo
Eun-Kyeong
EK
D005786:Gene Expression Regulation; D006801:Humans; D016753:Interleukin-10 / Q000502:physiology; D018664:Interleukin-12 / Q000378:metabolism; D053762:Interleukin-12 Subunit p40; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases; D051195:Toll-Like Receptor 2 / Q000378:metabolism / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000502:physiology
D016753:Interleukin-10; D018664:Interleukin-12; D053762:Interleukin-12 Subunit p40; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D021122:Protein Subunits; D051057:Proto-Oncogene Proteins c-akt; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D058570:TOR Serine-Threonine Kinases; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C508609:IL10 protein, human; C508840:IL23A protein, human; C495345:TLR4 protein, human; C546842:MTOR protein, human; C069329:RPS6KA1 protein, human