tailieunhanh - Báo cáo khoa học: Effect of 5-lipoxygenase inhibitor MK591 on early molecular and signaling events induced by staphylococcal enterotoxin B in human peripheral blood mononuclear cells

Staphylococcal enterotoxin B (SEB) has been the focus of a number of stu-dies due to its ability to promote septic shock and a massive impact on the human immune system. Even though symptoms and pathology associated with SEB is well known, early molecular events that lead to lethality are still poorly understood. | ễFEBS Journal Effect of 5-lipoxygenase inhibitor MK591 on early molecular and signaling events induced by staphylococcal enterotoxin B in human peripheral blood mononuclear cells Chanaka Mendis1 Katherine Campbell1 Rina Das2 David Yang3 and Marti Jett2 1 Department of Chemistry and Engineering Physics University of Wisconsin-Platteville WI USA 2 Department of Molecular Pathology Walter Reed Army Institute of Research Silver Spring MD USA 3 Department of Chemistry Georgetown University Washington DC USA Keywords cross-talk MK591 pathway interconnectors signal transduction staphylococcalenterotoxin B Correspondence C. Mendis Department of Chemistry and Engineering Physics University of Wisconsin-Platteville 308 Ottensman Hall 1 University Plaza Platteville WI USA Fax 1 608 342 1559 Tel 1 608 342 1692 E-mail mendisc@ Received 5 December 2007 revised 9 April 2008 accepted 11 April 2008 doi Staphylococcal enterotoxin B SEB has been the focus of a number of studies due to its ability to promote septic shock and a massive impact on the human immune system. Even though symptoms and pathology associated with SEB is well known early molecular events that lead to lethality are still poorly understood. Our approach was to utilize SEB induced human peripheral blood mononuclear cells PBMCs as a prototype module to further investigate the complexity of signaling cascades that may ultimately lead to lethal shock. Our study revealed the activation of multiple divergent intracellular pathways within minutes of SEB induction including components that interconnect investigated pathways. A series of performed inhibitor studies identified a specific inhibitor of 5-LO MK591 which has the ability to block JNK MAPK p38kinase and 5-LO signaling-cascades and drastically reducing the activity of pro-inflammatory cytokine TNF-a. Further evaluation of MK591 utilizing cell proliferation assays in PBMCs human proximal tubule cells and in vivo studies .

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