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.
Footnotes
This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant R01-DK05827] (to M.K.); the National Institutes of Health National Institute of General Medical Sciences [Grants R01-GM079360, R01-GM08096] (to F.I. and W.C., respectively); the National Institutes of Health National Heart, Lung, and Blood Institute [Grant NHLB-I1S10-RR022586 (to M.S.-C.)]; Shriners Hospitals for Children [Research Grants 85400, 71000] (to M.K.); and the American Heart Association [Grant 0755890T] (to W.C.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.183558.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- FT1–277
- N-[4-[2(R)-amino-3-mercaptopropyl]amino-2-phenylbenzoyl]methionine methyl ester trifluoroacetate salt
- FTI
- farnesyltransferase inhibitor
- LPS
- lipopolysaccharide
- CLP
- cecal ligation and puncture
- Tregs
- regulatory T cells
- TCR
- T-cell receptor
- Th1
- type 1 helper T cell
- PD-1
- programmed death-1
- PD-L1
- PD-1 ligand-1
- PBS
- phosphate-buffered saline
- TUNEL
- terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling
- IFN-γ
- interferon-γ
- IL-4
- interleukin-4
- DTT
- dithiothreitol
- PMSF
- phenylmethylsulfonyl fluoride
- ELISA
- enzyme-linked immunosorbent assay
- LV
- left ventricular
- LVIDs
- left ventricular end-systolic diameter
- Th2
- type 2 helper T cell
- HMGB1
- high-mobility group protein box 1
- RT-PCR
- reverse transcription-polymerase chain reaction
- CHAPS
- 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid.
- Received May 26, 2011.
- Accepted August 24, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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