Phospholipase C Activator m-3M3FBS Protects against Morbidity and Mortality Associated with Sepsis

Title
Phospholipase C Activator m-3M3FBS Protects against Morbidity and Mortality Associated with Sepsis
Author(s)
백석환김상두[김상두]김학정[김학정]심재웅[심재웅]이하영[이하영]이성균[이성균]권순일[권순일]정영수[정영수]박준성[박준성]Brian A Zabel[Brian A Zabel]배외식[배외식]
Keywords
INTERLEUKIN-1 RECEPTOR ANTAGONIST; INFLAMMATORY RESPONSE; INDUCED APOPTOSIS; CYTOKINE PROFILE; CECAL LIGATION; DOUBLE-BLIND; RESISTANCE; INFECTION; PUNCTURE; THERAPY
Issue Date
201208
Publisher
AMER ASSOC IMMUNOLOGISTS
Citation
JOURNAL OF IMMUNOLOGY, v.189, no.4, pp.2000 - 2005
Abstract
Although phospholipase C (PLC) is a crucial enzyme required for effective signal transduction and leukocyte activation, the role of PLC in polymicrobial sepsis remains unclear. In this study, we show that the direct PLC activator m-3M3FBS treatment significantly attenuates vital organ inflammation, widespread immune cell apoptosis, and mortality in a mouse sepsis model induced by lethal cecal ligation and puncture challenge. Mechanistically, m-3M3FBS-dependent protection was largely abolished by pretreatment of mice with the PLC-selective inhibitor U-73122, thus confirming PLC agonism by m-3M3FBS in vivo. PLC activation enhanced the bactericidal activity and hydrogen peroxide production of mouse neutrophils, and it also enhanced the production of IFN-gamma and IL-12 while inhibiting proseptic TNF-alpha and IL-1 beta production in cecal ligation and puncture mice. In a second model of sepsis, PLC activation also inhibited the production of TNF-alpha and IL-1 beta following systemic LPS challenge. In conclusion, we show that agonizing the central signal transducing enzyme PLC by m-3M3FBS can reverse the progression of toxic shock by triggering multiple protective downstream signaling pathways to maintain organ function, leukocyte survival, and to enhance microbial killing. The Journal of Immunology, 2012, 189: 2000-2005.
URI
http://hdl.handle.net/YU.REPOSITORY/27495http://dx.doi.org/10.4049/jimmunol.1200635
ISSN
0022-1767
Appears in Collections:
의과대학 > 생화학.분자생물학교실 > Articles
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