Immune Netw.
2005 Dec;5(4):237-246. 10.4110/in.2005.5.4.237.
The Phospholipase-Protein Kinase C-MEK-ERK Pathway is Essential in Mycobacteria-induced CCL3 and CCL4 Expression in Human Monocytes
- Affiliations
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- 1Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, Korea. hayoungj@cnu.ac.kr
- 2Department of Microbiology, College of Medicine, Konyang University, Nonsan, Korea.
- KMID: 1846711
- DOI: http://doi.org/10.4110/in.2005.5.4.237
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. Mycobacteria-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 (GO6976 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.
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