Phospholipase C activator m-3M3FBS protects against morbidity and mortality associated with sepsis.
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-γ and IL-12 while inhibiting proseptic TNF-α and IL-1β production in cecal ligation and puncture mice. In a second model of sepsis, PLC activation also inhibited the production of TNF-α and IL-1β 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.
Department of Biological Sciences, Sungkyunkwan University, Suwon 440-746, South Korea.
Sang Doo
SD
Kim
Hak Jung
HJ
Kim
Jae Woong
JW
Shim
Ha Young
HY
Lee
Sung Kyun
SK
Lee
Soonil
S
Kwon
Young Su
YS
Jung
Suk-Hwan
SH
Baek
Joon Seong
JS
Park
Brian A
BA
Zabel
Yoe-Sik
YS
Bae
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality; D013449:Sulfonamides / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000378:metabolism*; D000096926:Benzenesulfonamides
D016207:Cytokines; D013449:Sulfonamides; D010738:Type C Phospholipases; C473783:2,4,6-trimethyl-N-(meta-3-trifluoromethylphenyl)benzenesulfonamide; D000096926:Benzenesulfonamides