title: Heme oxygenase as a therapeutic target in immunological pregnancy complications.
abstract: The allogeneic fetus has been considered to be an allograft and the tolerance mechanisms involved in pregnancy maintenance resemble those leading to graft acceptance. Up-regulation of Heme Oxygenase-1 (HO-1) promotes graft acceptance. Additionally, HO-1 has been proposed to have tissue-protective properties. Previous studies reported the presence of HO-1 and HO-2 in mammalian placenta and postulated a protective role for HO during pregnancy. Here, we analyze HO-1 and HO-2 expression at the feto-maternal interface from normal pregnant and abortion mice and correlate these findings with inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) expression as well as with Th1/Th2 cytokine production by immune cells. DBA/2-mated CBA/J females undergoing abortion and BALB/c-mated CBA/J females having normal pregnancies were included in our study. The mice received no treatment. On day 14 of pregnancy, the mice were sacrificed, the abortion rate was calculated and the ex vivo Th1/Th2 production by decidual immune cells was analyzed by flow cytometry. The expression of HO-1 and HO-2, iNOS and eNOS was analyzed by immunohistochemistry (IHC) and Western blot in placenta samples. The Th1/Th2 cytokines ratio was augmented in decidua from abortion mice. We further observed a significant down-regulation of HO-1, HO-2, iNOS and eNOS molecules in placental tissue from mice undergoing abortion when compared to normal pregnant mice. Since we found diminished HOs and nitric oxide synthase (NOS) levels at the feto-maternal interface from abortion mice when compared to normal pregnant mice, which were further associated with increased Th1/Th2 cytokine production, we propose HO as a putative therapeutic target in immunological abortions. Up-regulation of HO-1 or HO-2 would favour the Th2-cytokine production, which could avoid abortion onset.
authors.affiliation: Institute of Medical Immunology, Charité, Medical University Berlin, Room 2.0534, Augustenburger Platz 1, 13353 Berlin, Germany. ana.zenclussen@charite.de
authors.forename: Ana Claudia
authors.initials: AC
authors.lastname: Zenclussen
authors.forename: Andre
authors.initials: A
authors.lastname: Sollwedel
authors.forename: Annarosa Zambon
authors.initials: AZ
authors.lastname: Bertoja
authors.forename: Katrin
authors.initials: K
authors.lastname: Gerlof
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Zenclussen
authors.forename: Christian
authors.initials: C
authors.lastname: Woiciechowsky
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Volk
mesh_terms: D000022:Abortion, Spontaneous / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D003656:Decidua / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D015536:Down-Regulation; D005260:Female; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D051547:Heme Oxygenase-1; D008565:Membrane Proteins; D008571:Men; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010920:Placenta / Q000201:enzymology* / Q000473:pathology; D011247:Pregnancy; D011248:Pregnancy Complications / Q000201:enzymology* / Q000276:immunology; D013154:Spleen / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D016207:Cytokines; D008565:Membrane Proteins; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C105245:heme oxygenase-2