Mycobacteria-induced Interleukin-12 Expression by Human Monocyte-derived Macrophages Is Negatively Regulated by Phosphatidylinositol 3-kinase and ERK 1/2 Pathways.
- Author:
Chul Su YANG
1
;
Ji Sook LEE
;
Chang Hwa SONG
;
Saet Byel JUNG
;
Kil Soo LEE
;
A Rum SHIN
;
Hwa Jung KIM
;
Jeong Kyu PARK
;
Tae Hyun PAIK
;
Eun Kyeong JO
Author Information
1. Department of Microbiology, College of Medicine, Chungnam National University, Daejeon 301-747, Korea. hayoungj@cnu.ac.kr
- Publication Type:Original Article
- Keywords:
Mycobacterium tuberculosis;
IL-12;
TNF-alpha;
PI 3-K;
ERK
- MeSH:
Humans*;
Interleukin-12*;
Interleukins;
Macrophages*;
MAP Kinase Signaling System;
Monocytes;
Mycobacterium tuberculosis;
Neptune;
Phosphatidylinositol 3-Kinase*;
Phosphatidylinositols*;
Phosphorylation;
Phosphotransferases;
Protein Kinases;
RNA, Messenger;
Tumor Necrosis Factor-alpha
- From:Journal of Bacteriology and Virology
2005;35(3):239-248
- CountryRepublic of Korea
- Language:English
-
Abstract:
Both interleukin (IL)-12, an important cytokine skewing the immune response towards a Th1 cytokine profiles, and tumor necrosis factor (TNF)-alpha, are thought to be critical factors in defenses against mycobacteria. In this study, we evaluated the roles of phosphatidylinositol 3-kinase (PI 3-K), and extracellular signal-regulated kinase (ERK) 1/2 pathways in the expression of IL-12 in human monocyte-derived macrophages (MDMs) after stimulation with Mycobacterium tuberculosis H37Rv (M. tbc) or the Triton X-114 solublized proteins (TSP) of M. tbc. Both M. tbc and TSP rapidly phosphorylated ERK 1/2, and Akt in human MDMs. Inhibition of PI 3-K-Akt pathway by specific inhibitors (LY294002 and wortmannin) dramatically increased M. tbc- or TSP-induced IL-12 p40 and p35 mRNA and IL-12 production. In addition, blockade of ERK 1/2 pathway by specific inhibitors (PD98059 and U0126) significantly increased the mRNA levels and cytokine production in M. tbc- or TSP-treated MDMs. On the contrary, M. tbc- or TSP-induced TNF-a production was significantly depressed in human MDMs by pretreatment with inhibitors of PI 3-K or ERK pathways. The M. tbc or TSP stimulation decreased ERK 1/2 phosphorylation by 70% in the presence of wortmannin or LY294002, suggesting that some cross-talk between the PI 3-K-Akt and mitogen-activated protein kinase kinase (MEK)-ERK pathways may be operating in human monocytes during mycobacterial infection. PI 3-K activity is partially required for the M. tbc- or TSP-induced ERK 1/2 phosphorylation. Collectively, these data suggest that the PI 3-K and ERK 1/2 pathways play a central role in the negative regulation of IL-12, but not TNF-a, production by M. tbc.
