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

• Published in: The Journal of immunology (1950) 2005-10, Vol.175 (8), p.4875-4885
• Main Authors: Sollwedel, Andre, Bertoja, Annarosa Zambon, Zenclussen, Maria Laura, Gerlof, Katrin, Lisewski, Ulrike, Wafula, Paul, Sawitzki, Birgit, Woiciechowsky, Christian, Volk, Hans-Dieter, Zenclussen, Ana Claudia
• Format: Article
• Language: English
• Subjects: Abortion, Spontaneous - metabolism; Abortion, Spontaneous - prevention & control; Animals; Biomarkers; Carrier Proteins - metabolism; DNA-Binding Proteins; Female; Heme Oxygenase-1 - physiology; Male; Maternal-Fetal Exchange - physiology; Mice; Mice, Inbred BALB C; Mice, Inbred CBA; Mice, Inbred DBA; Neuropilin-1 - metabolism; Nitric Oxide Synthase Type II - biosynthesis; Nitric Oxide Synthase Type II - genetics; Nitric Oxide Synthase Type III - biosynthesis; Nitric Oxide Synthase Type III - genetics; Pregnancy; Protoporphyrins - pharmacology; T-Lymphocytes, Regulatory - metabolism; Th2 Cells - metabolism; Transcription Factors; Up-Regulation - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.175.8.4875

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.