Expression of c-FLIP in a rat model of sepsis and its effects on endothelial apoptosis

Shen,Lei; Sun,Zhengda; Zhao,Feng; Wang,Wei; Zhang,Wenhong; Zhu,Hechen

doi:10.3892/mmr.2017.6564

Expression of c-FLIP in a rat model of sepsis and its effects on endothelial apoptosis

Authors:
- Lei Shen
- Zhengda Sun
- Feng Zhao
- Wei Wang
- Wenhong Zhang
- Hechen Zhu
View Affiliations

Affiliations: Department of Intensive Care Unit, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China, Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA 94143, USA, Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
Published online on: May 10, 2017 https://doi.org/10.3892/mmr.2017.6564
Pages: 231-237
Copyright: © Shen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Sepsis is characterized by the impaired regulation of inflammatory responses. Apoptosis is important in the pathogenesis of sepsis. Cellular FLICE‑inhibitory protein (c‑FLIP) is a catalytically inactive caspase‑8 homologue, which negatively interferes with apoptotic signaling. The role of c‑FLIP in sepsis and in endothelial cell apoptosis, a critical step in the pathogenesis of sepsis, remains controversial. In the present study, to investigate the relationship between c‑FLIP and sepsis, a rat model of sepsis was induced by cecal ligation and puncture, and western blot analysis was used to detect the expression of c‑FLIPL, the long isoform of c‑FLIP. Lower protein expression levels of c‑FLIPL were found in the brain, intestine and lung of the rat sepsis model, compared with the rats in the sham surgery group. The association between the expression of c‑FLIPL and endothelial cell apoptosis was further examined in vitro by c‑FLIPL overexpression and flow cytometry, which demonstrated that the expression of c‑FLIPL was inversely correlated with endothelial cell apoptosis. These data suggested that c‑FLIP may be important in sepsis and shed light on therapeutic strategies.

View Figures

View References

1	Yu JW and Shi Y: FLIP and the death effector domain family. Oncogene. 27:6216–6227. 2008. View Article : Google Scholar : PubMed/NCBI
2	Longley DB, Wilson TR, McEwan M, Allen WL, McDermott U, Galligan L and Johnston PG: c-FLIP inhibits chemotherapy-induced colorectal cancer cell death. Oncogene. 25:838–848. 2006. View Article : Google Scholar : PubMed/NCBI
3	Yan T, Li Q, Zhou H, Zhao Y, Yu S, Xu G, Yin Z, Li Z and Zhao Z: Gu-4 suppresses affinity and avidity modulation of CD11b and improves the outcome of mice with endotoxemia and sepsis. PLoS One. 7:e301102012. View Article : Google Scholar : PubMed/NCBI
4	Wang W, Zhao F, Fang Y, Li X, Shen L, Cao T and Zhu H: Glycyrrhizin protects against porcine endotoxemia through modulation of systemic inflammatory response. Crit Care. 17:R442013. View Article : Google Scholar : PubMed/NCBI
5	Krautwald S, Ziegler E, Tiede K, Pust R and Kunzendorf U: Transduction of the TAT-FLIP fusion protein results in transient resistance to Fas-induced apoptosis in vivo. J Biol Chem. 279:44005–44011. 2004. View Article : Google Scholar : PubMed/NCBI
6	Bagnoli M, Canevari S and Mezzanzanica D: Cellular FLICE-inhibitory protein (c-FLIP) signalling: A key regulator of receptor-mediated apoptosis in physiologic context and in cancer. Int J Biochem Cell Biol. 42:210–213. 2010. View Article : Google Scholar : PubMed/NCBI
7	Bannerman DD and Goldblum SE: Mechanisms of bacterial lipopolysaccharide-induced endothelial apoptosis. Am J Physiol Lung Cell Mol Physiol. 284:L899–L914. 2003. View Article : Google Scholar : PubMed/NCBI
8	Bannerman DD, Eiting KT, Winn RK and Harlan JM: FLICE-like inhibitory protein (FLIP) protects against apoptosis and suppresses NF-kappaB activation induced by bacterial lipopolysaccharide. Am J Pathol. 165:1423–1431. 2004. View Article : Google Scholar : PubMed/NCBI
9	Karahashi H, Michelsen KS and Arditi M: Lipopolysaccharide-induced apoptosis in transformed bovine brain endothelial cells and human dermal microvessel endothelial cells: The role of JNK. J Immunol. 182:7280–7286. 2009. View Article : Google Scholar : PubMed/NCBI
10	Rittirsch D, Huber-Lang MS, Flierl MA and Ward PA: Immunodesign of experimental sepsis by cecal ligation and puncture. Nat Protoc. 4:31–36. 2009. View Article : Google Scholar : PubMed/NCBI
11	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
12	Hunt MA, Currie MJ, Robinson BA and Dachs GU: Optimizing transfection of primary human umbilical vein endothelial cells using commercially available chemical transfection reagents. J Biomol Tech. 21:66–72. 2010.PubMed/NCBI
13	Safa AR, Day TW and Wu CH: Cellular FLICE-like inhibitory protein (C-FLIP): A novel target for cancer therapy. Curr Cancer Drug Targets. 8:37–46. 2008. View Article : Google Scholar : PubMed/NCBI
14	Perlman H, Pagliari LJ, Georganas C, Mano T, Walsh K and Pope RM: FLICE-inhibitory protein expression during macrophage differentiation confers resistance to fas-mediated apoptosis. J Exp Med. 190:1679–1688. 1999. View Article : Google Scholar : PubMed/NCBI
15	Coletta C, Módis K, Oláh G, Brunyánszki A, Herzig DS, Sherwood ER, Ungvári Z and Szabo C: Endothelial dysfunction is a potential contributor to multiple organ failure and mortality in aged mice subjected to septic shock: Preclinical studies in a murine model of cecal ligation and puncture. Crit Care. 18:5112014. View Article : Google Scholar : PubMed/NCBI
16	Ostrowski SR, Haase N, Müller RB, Møller MH, Pott FC, Perner A and Johansson PI: Association between biomarkers of endothelial injury and hypocoagulability in patients with severe sepsis: A prospective study. Crit Care. 19:1912015. View Article : Google Scholar : PubMed/NCBI