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Protection from Abortion by Heme Oxygenase-1 Up-Regulation Is Associated with Increased Levels of Bag-1 and Neuropilin-1 at the Fetal-Maternal Interface¹

Andre Sollwedel^3,*, Annarosa Zambon Bertoja^3,*, Maria Laura Zenclussen^*, Katrin Gerlof^*, Ulrike Lisewski^*, Paul Wafula^*, Birgit Sawitzki^*, Christian Woiciechowsky, Hans-Dieter Volk^* and Ana Claudia Zenclussen^2,*

^* Reproductive Immunology Group, Institute of Medical Immunology, Biomedizinisches Forschungszentrum (BMFZ), Charité Medical University of Berlin, Germany; and Neurosurgery, BMFZ, Charité Medical University of Berlin, Berlin, Germany

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.

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