The Phospholipase-Protein Kinase C-MEK-ERK Pathway is Essential in Mycobacteria-induced CCL3 and CCL4 Expression in Human Monocytes.
- Author:
Chul Su YANG
1
;
Chang Hwa SONG
;
Saet Byel JUNG
;
Kil Soo LEE
;
Su Young KIM
;
Ji Sook LEE
;
A Rum SHIN
;
Jae Hee OH
;
Yu Mi KWON
;
Hwa Jung KIM
;
Jeong Kyu PARK
;
Tae Hyun PAIK
;
Eun Kyeong JO
Author Information
- Publication Type:Original Article
- Keywords: Mycobacterium tuberculosis; monocyte; CCL3; CCL4; MAPK
- MeSH: Antibodies; Blotting, Western; Hand; Humans*; Monocytes*; Mycobacterium tuberculosis; Phosphorylation; Phosphotransferases*; Protein Kinase C; Protein Kinases; Signal Transduction; Type C Phospholipases
- From:Immune Network 2005;5(4):237-246
- CountryRepublic of Korea
- Language:Korean
- 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.
