Differential regulation of interleukin-12 and tumour necrosis factor-alpha by phosphatidylinositol 3-kinase and ERK 1/2 pathways during Mycobacterium tuberculosis infection.
Interleukin (IL)-12 and tumour necrosis factor (TNF)-alpha are both thought to be critical factors in the defence against mycobacteria but are known to play different roles. In this study, we investigated the regulatory pathways for IL-12 and TNF-alpha expression in human monocyte-derived macrophages (MDMs) after treatment with Mycobacterium tuberculosis H37Rv or the Triton X-100 solubilized proteins (TSP) purified from M. tuberculosis. We found a rapid phosphorylation of Akt and extracellular signal-regulated kinase (ERK), albeit with differential activation kinetics, in human MDMs treated with M. tuberculosis or TSP. Studies using inhibitors selective for phosphatidylinositol 3-kinase (PI 3-K) and ERK 1/2 show that both pathway plays an essential role in the induction of TNF-alpha at both the transcriptional and translational levels in human MDMs. In contrast, blockade of the PI 3-K/Akt or ERK 1/2 pathways significantly increased M. tuberculosis- or TSP-induced IL-12 p40 and p35 mRNA and bioactive p70 protein. The enhancement of IL-12 levels by inhibition of PI 3-K and ERK 1/2 was not reversed by neutralization of TNF-alpha or addition of rhTNF-alpha, suggesting that the negative regulation of IL-12 is not mediated by concomitant TNF-alpha suppression. Further, PI 3-K activity is required for the M. tuberculosis- or TSP-induced phosphorylation of ERK 1/2 activation. TSP from M. tuberculosis shows a similar dependency on the PI 3-K and ERK 1/2 pathways to those by M. tuberculosis. Collectively, these data suggest that the Th1-driving cytokine IL-12 and proinflammatory cytokine TNF-alpha are differentially regulated by PI 3-K and ERK 1/2 pathways in human MDMs during mycobacterial infection. These results may provide therapeutic targets for precise and specific fine-tuning of cytokine responses.
Yang
C-S
CS
Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, Korea.
Lee
J-S
JS
Jung
S-B
SB
Oh
J-H
JH
Song
C-H
CH
Kim
H-J
HJ
Park
J-K
JK
Paik
T-H
TH
Jo
E-K
EK
D000704:Analysis of Variance; D000730:Androstadienes / Q000494:pharmacology; D000942:Antigens, Bacterial / Q000276:immunology; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D018664:Interleukin-12 / Q000276:immunology*; D020935:MAP Kinase Signaling System; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009169:Mycobacterium tuberculosis / Q000276:immunology; D009570:Nitriles / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014376:Tuberculosis / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D000077191:Wortmannin
D000730:Androstadienes; D000942:Antigens, Bacterial; D002070:Butadienes; D002867:Chromones; D005419:Flavonoids; D018664:Interleukin-12; D020929:Mitogen-Activated Protein Kinase Kinases; D009025:Morpholines; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D000077191:Wortmannin; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one