The rLrp of Mycobacterium tuberculosis inhibits proinflammatory cytokine production and downregulates APC function in mouse macrophages via a TLR2-mediated PI3K/Akt pathway activation-dependent mechanism

We demonstrate that Mycobacterium tuberculosis recombinant leucine-responsive regulatory protein （rLrp） inhibits lipopolysaccharide （LPS）-induced tumor necrosis factor alpha （TNF-a）, interleukin-6, and interleukin-12 production and blocks the nuclear translocation of subunits of the nuclear-receptor...

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Published in:Cellular & molecular immunology 2016-11, Vol.13 (6), p.729-746
Main Authors: Liu, Yuan, Li, Jia-Yun, Chen, Su-Ting, Huang, Hai-Rong, Cai, Hong
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
Adenomatous polyposis coli
AKT protein
Amino acids
Animals
Antigen-Presenting Cells - drug effects
Antigen-Presenting Cells - immunology
Autophagosomes - drug effects
Autophagosomes - metabolism
Bacterial Proteins - metabolism
CD86 antigen
Cell Nucleus - drug effects
Cell Nucleus - metabolism
Cytokines
Cytokines - biosynthesis
Down-Regulation - drug effects
Glycogen
Glycogen synthase kinase 3
Glycogen Synthase Kinase 3 beta - metabolism
Immune response
Inflammation
Inflammation Mediators - metabolism
Interferon-gamma - pharmacology
Interleukin 1
Interleukin 12
Interleukin 6
Interleukin-1 Receptor-Associated Kinases
Kinases
Ligands
Lipopolysaccharides
Lipopolysaccharides - pharmacology
Macrophages
Macrophages - drug effects
Macrophages - metabolism
Major histocompatibility complex
MAP Kinase Kinase Kinases - metabolism
Mice
Mice, Inbred C57BL
Mycobacterium tuberculosis
Mycobacterium tuberculosis - metabolism
N-Terminus
NF-kappa B - metabolism
NF-κB protein
Nuclear transport
Phosphatidylinositol 3-Kinases - metabolism
Phosphorylation
Phosphorylation - drug effects
Protein Binding - drug effects
Protein Subunits - metabolism
Protein Transport - drug effects
Proto-Oncogene Proteins c-akt - metabolism
RAW 264.7 Cells
Signal Transduction - drug effects
TAK1 protein
TLR2 protein
TNF Receptor-Associated Factor 6 - metabolism
Toll-Like Receptor 2 - metabolism
Toll-like receptors
Tuberculosis
Tumor necrosis factor receptors
Tumor necrosis factor-TNF
γ-Interferon
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Summary:We demonstrate that Mycobacterium tuberculosis recombinant leucine-responsive regulatory protein （rLrp） inhibits lipopolysaccharide （LPS）-induced tumor necrosis factor alpha （TNF-a）, interleukin-6, and interleukin-12 production and blocks the nuclear translocation of subunits of the nuclear-receptor transcription factor NF-KB （Nuclear factor-kappa B）. Moreover, rLrp attenuated LPS-induced DNA binding and NF-κB transcriptional activity, which was accompanied by the degradation of inhibitory IκBα and a consequent decrease in the nuclear translocation of the NF-κB p65 subunit. RLrp interfered with the LPS-induced clustering of TNF receptor-associated factor 6 and with interleukin-1 receptor-associated kinase 1 binding to TAKI. Furthermore, rLrp did not attenuate proinflammatory cytokines or the expression of CD86 and major histocompatibility complex class-II induced by interferon-gamma in the macrophages of Toll-like receptor 2 deletion （TLR2-/-） mice and in protein kinase b （Akt）-depleted mouse cells, indicating that the inhibitory effects of rLrp were dependent on TLR2-mediated activation of the phosphatidylinositol 3-OH kinase （PI3K）/ Akt pathway. RLrp could also activate the PI3K/Akt pathway by stimulating the rapid phosphorylation of PI3K, Akt, and glycogen synthase kinase 3 beta in macrophages. In addition, 19 amino acid residues in the N-terminus of rLrp were determined to be important and required for the inhibitory effects mediated by TLR2. The inhibitory function of these 19 amino acids of rLrp raises the possibility that mimetic inhibitory peptides could be used to restrict innate immune responses in situations in which prolonged TLR signaling has deleterious effects. Our study offers new insight into the inhibitory mechanisms by which the TLR2-mediated PI3K/Akt pathway ensures the transient expression of potent inflammatory mediators.
ISSN:1672-7681
2042-0226
DOI:10.1038/cmi.2015.58