title: 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.
abstract: 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.
authors.affiliation: Reproductive Immunology Group, Institute of Medical Immunology, Biomedizinisches Forschungszentrum (BMFZ), Charité Medical University of Berlin, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Sollwedel
authors.forename: Annarosa Zambon
authors.initials: AZ
authors.lastname: Bertoja
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Zenclussen
authors.forename: Katrin
authors.initials: K
authors.lastname: Gerlof
authors.forename: Ulrike
authors.initials: U
authors.lastname: Lisewski
authors.forename: Paul
authors.initials: P
authors.lastname: Wafula
authors.forename: Birgit
authors.initials: B
authors.lastname: Sawitzki
authors.forename: Christian
authors.initials: C
authors.lastname: Woiciechowsky
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Volk
authors.forename: Ana Claudia
authors.initials: AC
authors.lastname: Zenclussen
mesh_terms: 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
chemical_list: 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