Differential regulation of interleukin-12 and tumour necrosis factor-alpha by phosphatidylinositol 3-kinase and ERK 1/2 pathways during Mycobacterium tuberculosis infection.

Abstract

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.

• Authors: C-S Yang, J-S Lee, S-B Jung, J-H Oh, C-H Song, H-J Kim, J-K Park, T-H Paik, E-K Jo
• Journal: Clinical and experimental immunology (Clin Exp Immunol) Vol. 143 Issue 1 Pg. 150-60 (Jan 2006) ISSN: 0009-9104 [Print] England
• PMID: 16367946 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Androstadienes
• Antigens, Bacterial
• Butadienes
• Chromones
• Flavonoids
• Morpholines
• Nitriles
• Phosphoinositide-3 Kinase Inhibitors
• Tumor Necrosis Factor-alpha
• U 0126
• Interleukin-12
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Mitogen-Activated Protein Kinase Kinases
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
• Wortmannin

Topics

• Analysis of Variance
• Androstadienes (pharmacology)
• Antigens, Bacterial (immunology)
• Butadienes (pharmacology)
• Cells, Cultured
• Chromones (pharmacology)
• Enzyme-Linked Immunosorbent Assay
• Flavonoids (pharmacology)
• Humans
• Interleukin-12 (immunology)
• MAP Kinase Signaling System
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors, metabolism)
• Morpholines (pharmacology)
• Mycobacterium tuberculosis (immunology)
• Nitriles (pharmacology)
• Phosphatidylinositol 3-Kinases (immunology)
• Phosphoinositide-3 Kinase Inhibitors
• Phosphorylation
• Reverse Transcriptase Polymerase Chain Reaction
• Tuberculosis (immunology)
• Tumor Necrosis Factor-alpha (immunology)
• Wortmannin