Placenta-derived CD95 ligand causes liver damage in hemolysis, elevated liver enzymes, and low platelet count syndrome.
OBJECTIVE
The HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome is a life-threatening complication during pregnancy. The associated liver disease may be severe, and maternal hepatic complications may progress to the point that transplantation becomes necessary. CD95 (APO-1, Fas)-mediated apoptosis of liver cells is one of the major pathogenic mechanisms during liver disease. The interaction of CD95 with its ligand, CD95L(FasL), induces apoptosis and thus the source of the death-inducing ligand is critical for understanding the pathomechanism of liver damage involving the CD95-system.


METHODS
Sera from HELLP patients were analyzed and used in cell culture experiments to study CD95-mediated apoptosis. We established a mouse model for placenta-induced liver damage and used a new therapeutical agent, LY498919, to block CD95 apoptosis.


RESULTS
We describe apoptosis in the liver of HELLP patients and cytotoxic activity for primary human hepatocytes in HELLP serum. Blocking of CD95 signaling reduced the cytotoxic activity of HELLP serum. In addition, cytotoxic activity increased as HELLP syndrome developed. Furthermore, CD95L was found to be produced in the placenta and extracts of placenta were cytotoxic for human hepatocytes. Injection of mouse placenta extract in mice induces liver damage that could be prevented by blocking CD95L.


CONCLUSIONS
Taken together, these data suggest that CD95L derived from the placenta acts systemically and is a primary cause of liver damage in HELLP syndrome. Our results also show that blocking of CD95L can reduce liver cell apoptosis, indicating that such a strategy may have therapeutic advantages.
Strand
Susanne
S
Department of Internal Medicine I, Johannes Gutenberg University, Mainz, Germany. sstrand@mail.uni-mainz.de
Strand
Dennis
D
Seufert
Rudolf
R
Mann
Amrit
A
Lotz
Johannes
J
Blessing
Manfred
M
Lahn
Michael
M
Wunsch
Andreas
A
Broering
Dieter C
DC
Hahn
Uwe
U
Grischke
Eva-Maria
EM
Rogiers
Xavier
X
Otto
Gerd
G
Gores
Gregory J
GJ
Galle
Peter R
PR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D053222:Fas Ligand Protein; D005260:Female; D017359:HELLP Syndrome / Q000097:blood / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D022781:Hepatocytes; D006801:Humans; D019169:Jurkat Cells; D008099:Liver / Q000473:pathology* / Q000503:physiopathology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008970:Molecular Weight; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D000637:Transaminases / Q000378:metabolism
C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D000637:Transaminases