Role of the Phosphatidylinositol 3-Kinase and Mitogen-Activated Protein Kinase Pathways in the Secretion of Tumor Necrosis Factor-α and Interleukin-10 by the PPD Antigen of Mycobacterium tuberculosis
Here we investigated the role of the phosphatidylinositol 3-kinase (PI 3-K) and mitogen-activated protein kinase (MAPK) pathways in the secretion of tumor necrosis factor (TNF)-α and interleukin (IL)-10 in human primary monocytes after stimulation with the PPD antigen of Mycobacterium tuberculosis. MAPK [extracellular signal-regulated kinase (ERK) 1/2 and p38] and Akt are rapidly phosphorylated in human monocytes stimulated with PPD. We found that the PI 3-K-Akt pathway stimulated by PPD is essential for both IL-10 and TNF-α production, although the inhibition of IL-10 production was more pronounced. The analysis of cytokine production using specific inhibitors of the MAPK pathway revealed that both p38 and ERK activation are essential for PPD-induced TNF-α production, whereas p38, but not ERK, activation is essential for IL-10 secretion. The inhibition of PI 3-K did not significantly activate p38 MAPK or ERK 1/2 in PPD-stimulated human monocytes. Further, the Src inhibitor PP2 inhibited the release of TNF-α but enhanced IL-10 release, suggesting the differential regulation of Src kinase in upstream signaling. Collectively, these data suggest that the PI 3-K and MAPK pathways play a central role in the regulation of both pro- and anti-inflammatory cytokines by the PPD antigen of M. tuberculosis.
KeywordsPPD antigen MAPK PI 3-K tumor necrosis factor-α interleukin-10
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- 4.Andersen AB, Brennan P: Proteins and antigens of Mycobacterium tuberculosis. In Tuberculosis: Pathogenesis, protection and control, Bloom BR (eds). Washington, DC, American Society for Microbiology, 1994, pp. 307–332Google Scholar
- 5.Weir RE, Fine PE, Nazareth B, Floyd S, Black GF, King E, Stanley C, Bliss L, Branson K, Dockrell HM: Interferon-gamma and skin test responses of schoolchildren in southeast England to purified protein derivatives from Mycobacterium tuberculosis and other species of mycobacteria. Clin Exp Immunol 134:285–294, 2003CrossRefPubMedGoogle Scholar
- 6.Weir RE, Black GF, Dockrell HM, Floyd S, Fine PE, Chaguluka SD, Stenson S, King E, Nazareth B, Warndorff DK, Ngwira B, Crampin AC, Mwaungulu L, Sichali L, Jarman E, Donovan L, Blackwell JM: Mycobacterial purified protein derivatives stimulate innate immunity: Malawians show enhanced tumor necrosis factor alpha, interleukin-1beta (IL-1beta), and IL-10 responses compared to those of adolescents in the United Kingdom. Infect Immun 72:1807–1811, 2004CrossRefPubMedGoogle Scholar
- 7.Garcia I, Miyazaki Y, Marchal G, Lesslauer W, Vassalli P: High sensitivity of transgenic mice expressing soluble TNFR1 fusion protein to mycobacterial infections: Synergistic action of TNF and IFN-gamma in the differentiation of protective granulomas. Eur J Immunol 27:3182–3190, 1997PubMedGoogle Scholar
- 16.Darieva Z, Lasunskaia EB, Campos MN, Kipnis TL, Da Silva WD: Activation of phosphatidylinositol 3-kinase and c-Jun-N-terminal kinase cascades enhances NF-kappaB-dependent gene transcription in BCG-stimulated macrophages through promotion of p65/p300 binding. J Leukoc Biol 75:689–697, 2004CrossRefPubMedGoogle Scholar
- 18.Song CH, Lee JS, Lee SH, Lim K, Kim HJ, Park JK, Paik TH, Jo EK: Role of mitogen-activated protein kinase pathways in the production of tumor necrosis factor-alpha, interleukin-10, and monocyte chemotactic protein-1 by Mycobacterium tuberculosis H37Rv-infected human monocytes. J Clin Immunol 23:194–201, 2003CrossRefPubMedGoogle Scholar
- 20.Dahle MK, Overland G, Myhre AE, Stuestol JF, Hartung T, Krohn CD, Mathiesen O, Wang JE, Aasen AO: The phosphatidylinositol 3-kinase/protein kinase B signaling pathway is activated by lipoteichoic acid and plays a role in Kupffer cell production of interleukin-6 (IL-6) and IL-10. Infect Immun 72:5704–5711, 2004CrossRefPubMedGoogle Scholar
- 26.Lee JS, Song CH, Lim JH, Kim HJ, Park JK, Paik TH, Kim CH, Kong SJ, Shon MH, Jung SS, Jo EK: The production of tumor necrosis factor-alpha is decreased in peripheral blood mononuclear cells from multidrug-resistant tuberculosis patients following stimulation with the 30-kDa antigen of Mycobacterium tuberculosis. Clin Exp Immunol 132:443–449, 2003CrossRefPubMedGoogle Scholar
- 28.Veres B, Gallyas F Jr, Varbiro G, Berente Z, Osz E, Szekeres G, Szabo C, Sumegi B: Decrease of the inflammatory response and induction of the Akt/protein kinase B pathway by poly-(ADP-ribose) polymerase 1 inhibitor in endotoxin-induced septic shock. Biochem Pharmacol 65:1373–1382, 2003CrossRefPubMedGoogle Scholar
- 33.Chan ED, Morris KR, Belisle JT, Hill P, Remigio LK, Brennan PJ, Riches DW: Induction of inducible nitric oxide synthase-NO* by lipoarabinomannan of Mycobacterium tuberculosis is mediated by MEK1-ERK, MKK7-JNK, and NF-kappaB signaling pathways. Infect Immun 69:2001–2010, 2001CrossRefPubMedGoogle Scholar