The Influence of Human Endotoxemia on CD95-Induced Apoptosis | Critical Care Medicine | JAMA Surgery | JAMA Network
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Bazzoni  FBeutler  B The tumor necrosis factor ligand and receptor families.  N Engl J Med. 1996;3341717- 1725Google ScholarCrossref
Lin  ECalvano  SELowry  SF The biologic control of systemic inflammatory response.  Curr Opin Crit Care. 1997;3299- 307Google ScholarCrossref
Liu  ZGHsu  HGoeddel  DVKarin  M Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis, while NF-κB activation prevents cell death.  Cell. 1996;87565- 576Google ScholarCrossref
van der Poll  TCalvano  SEKumar  A  et al.  Endotoxin induces downregulation of tumor necrosis factor receptors on circulating monocytes and granulocytes in humans.  Blood. 1995;862754- 2759Google Scholar
Calvano  SEvan der Poll  TCoyle  SMBarie  PSMoldawer  LLLowry  SF Monocyte tumor necrosis factor receptor levels as a predictor of risk in human sepsis.  Arch Surg. 1996;131434- 437Google ScholarCrossref
Lin  ECalvano  SELowry  SF Disordered apoptosis as a mechanism for adverse outcome.  Yearbook of Intensive Care and Emergency Medicine. New York, NY Springer-Verlag NY Inc1997;91- 99Google Scholar
Jimenez  MFWatson  RWGParodo  J  et al.  Dysregulated expression of neutrophil apoptosis in the systemic inflammatory response syndrome.  Arch Surg. 1997;1321263- 1270Google ScholarCrossref
Hsu  HXiong  JGoeddel  DV The TNF receptor 1-associated protein TRADD signals cell death and NF-κB activation.  Cell. 1995;81495- 504Google ScholarCrossref
Nagata  SGolstein  P The Fas death factor.  Science. 1995;2671449- 1456Google ScholarCrossref
Rudel  TBokoch  GM Membrane and morphological changes in apoptotic cells regulated by caspase-mediated activation of PAK2.  Science. 1997;2761571- 1574Google ScholarCrossref
Hesse  DGTracey  KJFong  Y  et al.  Cytokine appearance in human endotoxemia and primate bacteremia.  Surg Gynecol Obstet. 1988;166147- 153Google Scholar
Van Zee  KJDeForge  LEFischer  E  et al.  IL-8 in septic shock, endotoxemia, and after IL-1 administration.  J Immunol. 1991;1463478- 3482Google Scholar
van der Poll  TCoyle  SMLevi  M  et al.  Effect of a recombinant dimeric tumor necrosis factor receptor on inflammatory responses to intravenous endotoxin in normal humans.  Blood. 1997;893727- 3734Google Scholar
van der Poll  TCoyle  SMKumar  ABarbosa  KAgosti  JMLowry  SF Down-regulation of surface receptors for TNF and IL-1 on circulating monocytes and granulocytes during human endotoxemia.  J Immunol. 1997;1581490- 1497Google Scholar
Kischkel  FCHellbardt  SBehrmann  I  et al.  Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor.  EMBO J. 1995;145579- 5588Google Scholar
Zamzami  NMarchetti  PCastedo  M Reduction in mitochondrial potential constitutes an early irreversible step of programmed lymphocyte death in vivo.  J Exp Med. 1995;1811661- 1672Google ScholarCrossref
Enari  MSakahira  HYokoyama  HOkawa  KIwamatsu  ANagata  S A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD.  Nature. 1998;39143- 50Google ScholarCrossref
Squier  MKTSehnert  AJCohen  JJ Apoptosis in leukocytes.  J Leukoc Biol. 1995;572- 10Google Scholar
Van Zee  KJKohno  TFischer  ERock  CSMoldawer  LLLowry  SF Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor alpha in vitro and in vivo.  Proc Natl Acad Sci U S A. 1992;894845- 4849Google ScholarCrossref
Rogy  MACoyle  SMOldenburg  HSA  et al.  Persistently elevated soluble tumor necrosis factor receptor and interleukin-1 receptor antagonist levels in critically ill patients.  J Am Coll Surg. 1994;178132- 138Google Scholar
Goel  NUlrich  ETSt Clair  EWFleming  JALynch  DHSeldin  MF Lack of correlation between serum soluble Fas/APO-1 levels and autoimmune disease.  Arth Rheum. 1995;381738- 1743Google ScholarCrossref
Midis  GPShen  YOwen-Schaub  LB Elevated soluble Fas (sFas) levels in nonhematopoietic human malignancy.  Cancer Res. 1996;563870- 3874Google Scholar
Papoff  GCascino  IEramo  AStarace  GLynch  DHRuberti  G An N-terminal domain shared by Fas/Apo-1 (CD95) soluble variants prevents cell death in vitro.  J Immunol. 1996;1564622- 4630Google Scholar
Um  HDOrenstein  JMWahl  SM Fas mediates apoptosis in human monocytes by a reactive oxygen intermediate dependent pathway.  J Immunol. 1996;1563469- 3477Google Scholar
Nagata  S Apoptosis by death factor.  Cell. 1997;88355- 365Google ScholarCrossref
Tanaka  MSuda  THaze  K  et al.  Fas ligand in human serum.  Nat Med. 1996;2317- 322Google ScholarCrossref
Ogasawara  JWatanabe-Fukunaga  RAdachi  M  et al.  Lethal effect of the anti-Fas antibody in mice.  Nature. 1993;364806- 809Google ScholarCrossref
Tanaka  MItai  TAdachi  MNagata  S Downregulation of Fas ligand by shedding.  Nat Med. 1998;431- 36Google ScholarCrossref
Tanaka  MSuda  TTakahashi  TNagata  S Expression of the functional soluble form of human Fas ligand in activated lymphocytes.  EMBO J. 1995;141129- 1135Google Scholar
Grell  MDouni  EWajant  H  et al.  The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor.  Cell. 1995;83793- 802Google ScholarCrossref
Peter  MEHellbardt  SSchwartz-Albiez  R  et al.  Cell surface sialylation plays a role in modulating sensitivity towards APO-1-mediated apoptotic cell death.  Cell Death Differ. 1995;2163- 171Google Scholar
Leist  MGantner  FJilg  SWendel  A Activation of the 55 kDa TNF receptor is necessary and sufficient for TNF-induced liver failure, hepatocyte apoptosis, and nitrite release.  J Immunol. 1995;1541307- 1316Google Scholar
Muschen  MWarskulat  UDouillard  PGilbert  EHaussinger  D Regulation of CD95 (APO-1/Fas) receptor and ligand expression by lipopolysaccharide and dexamethasone in parenchymal and nonparenchymal rat liver cells.  Hepatology. 1998;27200- 208Google ScholarCrossref
Cheng  JZhou  TLiu  C  et al.  Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule.  Science. 1994;2631759- 1762Google ScholarCrossref
Krams  SMFox  CKBeatty  R  et al.  Human hepatocytes produce an isoform of Fas that inhibits apoptosis.  Transplantation. 1998;65713- 721Google ScholarCrossref
December 1998

The Influence of Human Endotoxemia on CD95-Induced Apoptosis

Author Affiliations

From the Department of Surgery, Division of Surgical Sciences, Robert Wood Johnson Medical School, New Brunswick, NJ (Drs Lin, Calvano, Randhawa, and Lowry, Ms Coyle, and Messrs Shahin and Kumar) and the Department of Surgery, New York University Medical Center, New York (Dr Katz).

Arch Surg. 1998;133(12):1322-1327. doi:10.1001/archsurg.133.12.1322

Background  The responses of monocyte and neutrophil tumor necrosis factor receptor type 1 (TNFR-1) and TNFR-2 during systemic inflammation have been described previously. Several other members of the TNFR superfamily also appear to have regulatory roles in immunocyte function, including apoptosis. However, the response of these other receptor members, such as CD95, to systemic inflammation is unclear.

Objectives  To compare the response of CD95 with that of TNFR during systemic inflammation and to assess the influence of the inflammatory milieu on CD95 function.

Setting  Adult clinical research center of a university hospital.

Subjects and Methods  Five healthy male subjects were administered intravenous endotoxin (2 ng/kg), and systemic response was measured by cytokine analysis and receptor expression assays during a 48-hour period. CD95 function during systemic inflammation was assessed using a Jurkat cell bioassay for degree of apoptosis.

Results  Monocyte and neutrophil CD95 expression exhibited changes parallel to that of TNFR following endotoxin injection. In contrast to soluble TNFR, which was transiently elevated during endotoxemia, soluble CD95 levels remained unchanged from baseline. Jurkat cells incubated in normal and postendotoxin serum samples equally exhibited less than 10% spontaneous apoptosis. No soluble CD95 ligand was detectable in experimental human endotoxemia.

Conclusions  Cell-associated CD95 exhibited changes parallel to its receptor family member TNFR following endotoxin administration. Soluble CD95 is present in human serum samples, but the levels remained unchanged following endotoxin administration. No soluble CD95 ligand activity was detectable by enzyme-linked immunosorbent assay or by functional assay. The potential protective role of soluble CD95 in human serum samples against CD95 ligand–induced apoptosis remains to be defined.