Phospholipase C activator m-3M3FBS protects against morbidity and mortality associated with sepsis.

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-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.

• Authors: Sang Doo Kim, Hak Jung Kim, Jae Woong Shim, Ha Young Lee, Sung Kyun Lee, Soonil Kwon, Young Su Jung, Suk-Hwan Baek, Joon Seong Park, Brian A Zabel, Yoe-Sik Bae
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 189 Issue 4 Pg. 2000-5 (Aug 15 2012) ISSN: 1550-6606 [Electronic] United States
• PMID: 22798676 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2,4,6-trimethyl-N-(meta-3-trifluoromethylphenyl)benzenesulfonamide
• Cytokines
• Sulfonamides
• Type C Phospholipases

Topics

• Animals
• Apoptosis (drug effects)
• Cytokines (biosynthesis)
• Disease Models, Animal
• Enzyme Activation (drug effects, physiology)
• Immunohistochemistry
• In Situ Nick-End Labeling
• Male
• Mice
• Mice, Inbred ICR
• Neutrophils (drug effects, immunology, metabolism)
• Sepsis (drug therapy, metabolism, mortality)
• Sulfonamides (pharmacology)
• Type C Phospholipases (metabolism)