Over-expression of heme oxygenase-1 by adenoviral gene transfer improves pregnancy outcome in a murine model of abortion.
Mammalian pregnancy is a complex phenomenon allowing the maternal immune system to support its allogeneic fetus. Physiological pathways protecting the fetus from rejection are thought to be comparable with those leading to allograft acceptance. Heme oxygenase (HO)-1 is known to protect locally against rejection in transplantation models due to its anti-oxidant, anti-inflammatory and cytoprotective functions. Based on previous data on low HO-1 levels in placenta from mice undergoing abortion, we hypothesized that an up-regulation of HO-1 during pregnancy would avoid fetal rejection in the murine abortion combination CBA/J x DBA/2J, using BALB/c-mated CBA/J as normal controls. We injected pregnant mice undergoing abortion with 1 x 10(5) PFU of an adenoviral vector containing HO-1 and GFP (AdHO-1/GFP), and compared the pregnancy outcome with PBS- or 1 x 10(5) AdEGFP-treated abortion-prone mice and with PBS-treated normal pregnant mice. The abortion rate diminished significantly after adenoviral gene transfer of AdHO-1/GFP. The systemic and local IL-4/IFN-gamma ratio was augmented in AdHO-1-treated mice compared to abortion-prone mice. Interestingly, the HO-1 treatment up-regulated the ratio IL-10/TNF-alpha in spleen but not in decidual lymphocytes. HO-1-treated mice further showed diminished apoptosis rate and increased Bag-1 mRNA levels at the materno-fetal interface. Thus, we propose HO-1 as a key regulator of pregnancy success. HO-1 would exert its action by locally up-regulating the Th2/Th1 cytokine ratio and by further protecting tissues from apoptosis.
Zenclussen
Maria Laura
ML
Institute of Medical Immunology, BMFZ, Charité, Medicine University of Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
Anegon
Ignacio
I
Bertoja
Annarosa Zambon
AZ
Chauveau
Christine
C
Vogt
Katrin
K
Gerlof
Katrin
K
Sollwedel
André
A
Volk
Hans-Dieter
HD
Ritter
Thomas
T
Zenclussen
Ana Claudia
AC
D000022:Abortion, Spontaneous / Q000276:immunology / Q000517:prevention & control*; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D016207:Cytokines / Q000096:biosynthesis; D004247:DNA / Q000032:analysis; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000235:genetics*; D008099:Liver / Q000737:chemistry; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D010920:Placenta / Q000737:chemistry / Q000166:cytology; D011247:Pregnancy; D011256:Pregnancy Outcome; D012333:RNA, Messenger / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics; D015854:Up-Regulation
C091732:BCL2-associated athanogene 1 protein; D016207:Cytokines; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D004247:DNA; D051547:Heme Oxygenase-1