Role of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways in the secretion of tumor necrosis factor-alpha 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)-alpha 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-alpha 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-alpha 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-alpha 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.
Jung
Saet-Byel
SB
Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, South Korea.
Song
Chang-Hwa
CH
Yang
Chul-Su
CS
Kim
Su-Young
SY
Lee
Kil-Soo
KS
Shin
A-Rum
AR
Lee
Ji-Sook
JS
Nam
Hae Sung
HS
Kim
Hwa-Jung
HJ
Park
Jeong-Kyu
JK
Paik
Tae-Hyun
TH
Jo
Eun-Kyeong
EK
D000942:Antigens, Bacterial; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000032:analysis / Q000096:biosynthesis*; D020935:MAP Kinase Signaling System / Q000276:immunology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D009000:Monocytes / Q000276:immunology* / Q000382:microbiology; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015290:Second Messenger Systems / Q000276:immunology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis*; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism; D019061:src-Family Kinases / Q000276:immunology / Q000378:metabolism
D000942:Antigens, Bacterial; D048049:Extracellular Signal-Regulated MAP Kinases; D016753:Interleukin-10; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D019061:src-Family Kinases; C412423:DPPD protein, Mycobacterium tuberculosis