• Title/Summary/Keyword: manumycin

Search Result 2, Processing Time 0.018 seconds

The Phospholipase-Protein Kinase C-MEK-ERK Pathway is Essential in Mycobacteria-induced CCL3 and CCL4 Expression in Human Monocytes (사람 단핵구에서 결핵균에 의해 유도되는 CCL3 및 CCL4 발현에 대한 Phospholipase-Protein Kinase C-MEK-ERK 경로의 역할 분석)

  • Yang, Chul-Su;Song, Chang-Hwa;Jung, Saet-Byel;Lee, Kil-Soo;Kim, Su-Young;Lee, Ji-Sook;Shin, A-Rum;Oh, Jae-Hee;Kwon, Yu-Mi;Kim, Hwa-Jung;Park, Jeong-Kyu;Paik, Tae-Hyun;Jo, Eun-Kyeong
    • IMMUNE NETWORK
    • /
    • v.5 no.4
    • /
    • pp.237-246
    • /
    • 2005
  • 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.