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The Phospholipase-Protein Kinase C-MEK-ERK Pathway is Essential in Mycobacteria-induced CCL3 and CCL4 Expression in Human Monocytes  

Yang, Chul-Su (Department of Microbiology, College of Medicine, Chungnam National University)
Song, Chang-Hwa (Department of Microbiology, College of Medicine, Chungnam National University)
Jung, Saet-Byel (Department of Microbiology, College of Medicine, Chungnam National University)
Lee, Kil-Soo (Department of Microbiology, College of Medicine, Chungnam National University)
Kim, Su-Young (Department of Microbiology, College of Medicine, Chungnam National University)
Lee, Ji-Sook (Department of Microbiology, College of Medicine, Konyang University)
Shin, A-Rum (Department of Microbiology, College of Medicine, Chungnam National University)
Oh, Jae-Hee (Department of Microbiology, College of Medicine, Chungnam National University)
Kwon, Yu-Mi (Department of Microbiology, College of Medicine, Chungnam National University)
Kim, Hwa-Jung (Department of Microbiology, College of Medicine, Chungnam National University)
Park, Jeong-Kyu (Department of Microbiology, College of Medicine, Chungnam National University)
Paik, Tae-Hyun (Department of Microbiology, College of Medicine, Konyang University)
Jo, Eun-Kyeong (Department of Microbiology, College of Medicine, Chungnam National University)
Publication Information
IMMUNE NETWORK / v.5, no.4, 2005 , pp. 237-246 More about this Journal
Abstract
Background: Little information is available on the identification and characterization of the upstream regulators of the signal transduction cascades for Mycobacterium tuberculosis (M. tbc)-induced ERK 1/2 activation and chemokine expression. We investigated the signaling mechanisms involved in expression of CCL3 /MIP-1 and CCL4/MIP-1 in human primary monocytes infected with M. tbc. Methods: MAP kinase phosphorylation was determined using western blot analysis with specific primary antibodies (ERK 1/2, and phospho-ERK1/2), and the upstream signaling pathways were further investigated using specific inhibitors. Results: An avirulent strain, M. tbc H37Ra, induced greater and more sustained ERK 1/2 phosphorylation, and higher CCL3 and CCL4 production, than did M. tbc H37Rv. Specific inhibitors for mitogen-activated protein kinase (MAPK) kinase (MEK; U0126 and PD98059) significantly inhibited the expression of CCL3 and CCL4 in human monocytes. Mycobactetia-mediated expression of CCL3 and CCL4 was not inhibited by the Ras inhibitor manumycin A or the Raf-1 inhibitor GW 5074. On the other hand, phospholipase C (PLC) inhibitor (U73122) and protein kinase C (PKC)specific inhibitors ($G\ddot{o}6976$ and Ro31-8220) significantly reduced M. tbc-induced activation of ERK 1/2 and chemokine synthesis. Conclusion: These results are the first to demonstrate that the PLC-PKC-MEK-ERK, not the Ras-Raf-MEK-ERK, pathway is the major signaling pathway inducing M. tbc-mediated CCL3 and CCL4 expression in human primary monocytes.
Keywords
Mycobacterium tuberculosis; monocyte; CCL3; CCL4; MAPK;
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