The dual functions of receptor interacting protein 1 in fas-induced hepatocyte death during sepsis.
In examining the liver's response to sepsis, our laboratory has found that septic hepatocytes exhibit a higher degree of necrosis when compared with septic thymocytes, which typically die through the canonical apoptotic pathway. Recently, an adaptor protein associated with the Fas/TNF death receptor pathway, receptor interacting protein 1 (RIP1), has been shown to be critical for determining whether a cell's death is apoptotic or necrotic. We propose to test the central hypothesis that RIP1 activation by death receptor (Fas) during sepsis determines whether the hepatocytes' fate is apoptotic versus necrotic. We approached this problem by delivering RIP1 siRNA in vivo to C57BL/6 mice and observing changes in mortality after septic challenge. Contrary to our hypothesis, RIP1-silenced mice did not survive as long as scrambled sequence injected controls (22.2% vs. 50.0% 14 days after cecal ligation and puncture, respectively). When we used a pharmacological/synthetic antagonist of RIP1 kinase, necrostatin 1 (Nec1), and examined the mortality of Nec1-treated mice, there was no difference from the RIP1 siRNA-treated mice (20.0% vs. 22.2%, respectively). Furthermore, we carried out a series of comparative histological studies, which indicated that septic mice pretreated with Nec1 exhibited a preservation of liver glycogen stores (represented by periodic acid Schiff stain) versus siRNA-treated mice, which exhibit lower glycogen stores as well as altered morphology. Furthermore, the histological studies also revealed that Nec1 treatment in septic mice increases caspase 3 activity. We speculate that these contradictatory findings are due to the dual-signaling responsibilities of RIP1, where the RIP1 kinase domain can induce death through Fas ligation while also initiating prosurvival signaling through nuclear factor κB (NF-κB).
Division of Surgical Research/Department of Surgery, Rhode Island Hospital, Providence, Rhode Island, USA.
Sam I
SI
McNeal
Mark P
MP
LeGolvan
Chun-Shiang
CS
Chung
Alfred
A
Ayala
D000818:Animals; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D047468:Immunoprecipitation; D007211:Indoles / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008112:Liver Glycogen / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D034741:RNA, Small Interfering; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018805:Sepsis / Q000235:genetics / Q000378:metabolism*
D007093:Imidazoles; D007211:Indoles; D008112:Liver Glycogen; D016328:NF-kappa B; D034741:RNA, Small Interfering; C507699:necrostatin-1; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D053148:Caspase 3
Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10923-7
8855284
J Biol Chem. 2010 Jan 8;285(2):969-78
19910467
Cell. 2009 Jul 23;138(2):229-32
19632174
Nat Med. 2003 Mar;9(3):347-51
12579197
Nat Immunol. 2000 Dec;1(6):489-95
11101870
Blood. 2005 Oct 1;106(7):2295-301
15941915
Cardiovasc Drugs Ther. 2007 Dec;21(6):467-9
17965927
J Surg Res. 1998 May;76(2):165-73
9698518
Cell Death Differ. 2010 Jan;17(1):35-45
19680262
Science. 2009 Jul 17;325(5938):332-6
19498109
EMBO J. 2010 Feb 3;29(3):619-31
19959994
Cell. 1995 May 19;81(4):513-23
7538908
Am J Pathol. 2010 Oct;177(4):1834-47
20709805
Nat Chem Biol. 2008 May;4(5):313-21
18408713
Surgery. 1983 Aug;94(2):331-5
6879447
Am J Pathol. 2007 Jul;171(1):87-96
17591956
FASEB J. 2009 Jun;23(6):1817-25
19158156
Blood. 1996 May 15;87(10):4261-75
8639785
Cell Death Differ. 2010 Jan;17(1):14-24
19893571
Trends Biochem Sci. 2008 Aug;33(8):352-5
18635359
Sci Signal. 2010 Mar 30;3(115):re4
20354226
Cell. 2009 Jun 12;137(6):1112-23
19524513
J Immunol. 1997 Jan 1;158(1):287-93
8977201