Farnesyltransferase inhibitor FTI-277 reduces mortality of septic mice along with improved bacterial clearance.

Abstract

Treatment with statins, inhibitors of HMG-CoA reductase, extends the survival of septic mice. However, the molecular mechanisms underlying the cholesterol-lowering, independent beneficial effects of statins in sepsis are poorly understood. The inhibition of protein isoprenylation, namely farnesylation and geranylgeranylation, has been proposed as a mediator of the pleiotropic protective effects of statins, although direct evidence is lacking. Major features of sepsis-induced immune suppression include T-cell dysfunction, which is characterized by apoptosis of splenic T cells, increased CD4(+)Foxp3(+) regulatory T cells (Tregs), and suppression of type 1 helper T-cell response [e.g., interferon-γ (IFN-γ) secretion] in mice. Here, we show that the induction of sepsis by cecal ligation and puncture (CLP) resulted in increases in farnesyltransferase activity and farnesylated proteins in the spleen relative to sham operation. Treatment with farnesyltransferase inhibitor N-[4-[2(R)-amino-3-mercaptopropyl]amino-2-phenylbenzoyl]methionine methyl ester trifluoroacetate salt (FTI-277) (25 mg/kg b.wt. i.p.) at 2 h after CLP blocked the increase in farnesylated proteins and improved survival and bacterial clearance of septic mice. FTI-277 reverted to or mitigated sepsis-induced apoptosis in spleen and thymus, increased splenic CD4(+)Foxp3(+) Tregs, and suppressed IFN-γ secretion and proliferation of splenocytes in response to anti-CD3+CD28 antibodies in mice. Moreover, FTI-277 promoted macrophage phagocytotic activity in septic mice. These results indicate that elevation in protein farnesylation plays a role in derangements in immune function and mortality of septic mice. These findings suggest that prevention of immune dysfunction might contribute to FTI-277-induced improvement in survival of septic mice. These data highlight protein farnesyltransferase as a novel potential molecular target to reduce the mortality of patients with sepsis.

• Authors: Wen Yang, Marina Yamada, Yoshiaki Tamura, Kyungho Chang, Ji Mao, Lin Zou, Yan Feng, Kotaro Kida, Marielle Scherrer-Crosbie, Wei Chao, Fumito Ichinose, Yong-Ming Yu, Alan J Fischman, Ronald G Tompkins, Shanglong Yao, Masao Kaneki
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 339 Issue 3 Pg. 832-41 (Dec 2011) ISSN: 1521-0103 [Electronic] United States
• PMID: 21873557 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Enzyme Inhibitors
• FTI 277
• HMGB1 Protein
• Methionine
• Farnesyltranstransferase

Topics

• Animals
• Bacterial Load (drug effects)
• Cecum (surgery)
• Cytokines (analysis)
• Drug Evaluation, Preclinical
• Enzyme Inhibitors (pharmacology)
• Farnesyltranstransferase (antagonists & inhibitors, metabolism)
• HMGB1 Protein (blood)
• Heart Function Tests
• Hemodynamics (drug effects)
• Lung (drug effects)
• Male
• Methionine (analogs & derivatives, pharmacology)
• Mice
• Mice, Inbred C57BL
• Protein Prenylation
• Sepsis (drug therapy, immunology, mortality)
• Spleen (drug effects, metabolism)
• T-Lymphocytes (drug effects)