Protection from abortion by heme oxygenase-1 up-regulation is associated with increased levels of Bag-1 and neuropilin-1 at the fetal-maternal interface.
Tolerance mechanisms allowing pregnancy success resemble those involved in allograft acceptance. Heme oxygenase (HO) is a tissue-protective molecule, which allows graft acceptance and is known to have antiapoptotic effects on several cell types. We previously reported down-regulated levels of HO-1 and HO-2 in placenta from allopregnant mice undergoing abortion. In this study, we analyzed whether the up-regulation of HO-1 by cobalt-protoporphyrin (Co-PP) during implantation window can rescue mice from abortion. Induction of HO-1 by Co-PP treatment prevented fetal rejection, whereas the down-regulation of HOs by zinc-protoporphyrin application boosted abortion. The beneficial effect of HO-1 induction was not related to a local shift to Th2-profile or to a change in the NO system. Interestingly, the expression of the antiapoptotic/cytoprotective molecule Bag-1 as well as the levels of neuropilin-1, a novel marker for T regulatory cells, were up-regulated after Co-PP treatment. Our data strongly support a very important role for HO-1 in fetal allotolerance and suggest that HO-1 might be protective by up-regulating tissue protective molecules, i.e., Bag-1, and by activating T regulatory cells rather than by changing the local cytokine profile.
Sollwedel
Andre
A
Reproductive Immunology Group, Institute of Medical Immunology, Biomedizinisches Forschungszentrum (BMFZ), Charité Medical University of Berlin, Germany.
Bertoja
Annarosa Zambon
AZ
Zenclussen
Maria Laura
ML
Gerlof
Katrin
K
Lisewski
Ulrike
U
Wafula
Paul
P
Sawitzki
Birgit
B
Woiciechowsky
Christian
C
Volk
Hans-Dieter
HD
Zenclussen
Ana Claudia
AC
D000022:Abortion, Spontaneous / Q000378:metabolism* / Q000517:prevention & control; D000818:Animals; D015415:Biomarkers; D002352:Carrier Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins; D005260:Female; D051547:Heme Oxygenase-1 / Q000502:physiology*; D008297:Male; D008431:Maternal-Fetal Exchange / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D039942:Neuropilin-1 / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis / Q000235:genetics; D011247:Pregnancy; D011524:Protoporphyrins / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism; D018418:Th2 Cells / Q000378:metabolism; D014157:Transcription Factors; D015854:Up-Regulation / Q000502:physiology
C091732:BCL2-associated athanogene 1 protein; D015415:Biomarkers; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D011524:Protoporphyrins; D014157:Transcription Factors; D039942:Neuropilin-1; C007095:cobaltiprotoporphyrin; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D051547:Heme Oxygenase-1