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

• Published in: Clinical and experimental immunology 2006-01, Vol.143 (1), p.150-160
• Main Authors: Yang, C.‐S., Lee, J.‐S., Jung, S.‐B., Oh, J.‐H., Song, C.‐H., Kim, H.‐J., Park, J.‐K., Paik, T.‐H., Jo, E.‐K.
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Androstadienes - pharmacology; Antigens, Bacterial - immunology; Biological and medical sciences; Butadienes - pharmacology; Cells, Cultured; Chromones - pharmacology; Clinical Studies; Enzyme-Linked Immunosorbent Assay; ERK; Flavonoids - pharmacology; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Humans; IL‐12; Immunopathology; Interleukin-12 - immunology; MAP Kinase Signaling System; Medical sciences; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinase Kinases - metabolism; Morpholines - pharmacology; Mycobacterium tuberculosis; Mycobacterium tuberculosis - immunology; Nitriles - pharmacology; Phosphatidylinositol 3-Kinases - immunology; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; PI 3‐K; Reverse Transcriptase Polymerase Chain Reaction; TNF‐α; Tuberculosis - immunology; Tumor Necrosis Factor-alpha - immunology; Wortmannin
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1111/j.1365-2249.2005.02966.x

Summary Interleukin (IL)‐12 and tumour necrosis factor (TNF)‐α 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‐α 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‐α 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‐α or addition of rhTNF‐α, suggesting that the negative regulation of IL‐12 is not mediated by concomitant TNF‐α 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‐α 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.