Download PDF
Horm Metab Res 2018; 50(02): 168-174
DOI: 10.1055/s-0043-120064
Endocrine Research
© Georg Thieme Verlag KG Stuttgart · New York

PreImplantation Factor (PIF*) Regulates Stress-Induced Adrenal Steroidogenesis and Anti-Inflammatory Cytokines: Potential Application for Bioartificial Adrenal Transplant

Mariya Balyura   #
1   Dept. of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
,
Evgeny Gelfgat   #
1   Dept. of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
,
Enrico Ullmann
1   Dept. of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
2   Department for Child and Adolescence Psychiatry, Psychotherapy and Psychosomatics, University of Leipzig, Leipzig, Germany
,
Barbara Ludwig
1   Dept. of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
3   Paul Langerhans Institute Dresden of Helmholtz Centre Munich at University Clinic Carl Gustav Carus of TU Dresden Faculty of Medicine, Technische Universität Dresden, DZD-German Centre for Diabetes Research, Dresden, Germany
4   Center for Regenerative Therapies, Technische Universität Dresden, Dresden, Germany
,
Eytan R. Barnea
5   BioIncept LLC, New York, NY, USA
6   SIEP, Society for the Investigation of Early Pregnancy, New York, NY, USA
,
Stefan R. Bornstein
1   Dept. of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
3   Paul Langerhans Institute Dresden of Helmholtz Centre Munich at University Clinic Carl Gustav Carus of TU Dresden Faculty of Medicine, Technische Universität Dresden, DZD-German Centre for Diabetes Research, Dresden, Germany
4   Center for Regenerative Therapies, Technische Universität Dresden, Dresden, Germany
7   Diabetes and Nutritional Sciences Division, King’s College London, London, UK
› Author Affiliations
Further Information

Publication History

received 21 June 2017

accepted 13 September 2017

Publication Date:
24 October 2017 (online)

Also available at
    Permissions and Reprints

Abstract

The main treatment algorithm for adrenal insufficiency is hormonal replacement, however, inadequate hormone substitution often leads to severe side effects. Adrenal cell transplantation could be a more effective alternative but would require life-long immune suppressive therapy. PreImplantation Factor (PIF) is an endogenous peptide secreted by viable human embryos that leads to maternal tolerance without immunosuppression. PIF could be effective for xenogeneic cell transplantation such as of bovine adrenocortical cells (BAC), which are used for bioartificial adrenal gland development that may more effectively restore complex adrenal functions. We report here that PIF exerts a dual regulatory effect on BAC by targeting mostly hyper-activated cells to specifically reduce adrenocorticotropic hormone (ACTH)-stimulated cortisol secretion. Reverse transcription real time PCR analysis revealed that PIF modulates the expression of two genes in the cortisol synthesis pathway, Steroidogenic Factor 1 (SF1), an activator of steroidogenesis, and the downstream steroidogenic enzyme Cytochrome P450 17A1 (CYP17A1). PIF increased basal expression of SF1 and CYP17A1 regardless of the activation level of the adrenocortical cells. In contrast, following ACTH stimulation, PIF reduced SF1 expression and induced expression of the immune suppressing anti-inflammatory cytokine IL10 only in the hyper-activated cells, suggesting both a protective and immune tolerant function. In conclusion, PIF regulates stress-induced adrenal steroidogenesis and immune tolerance in BAC, supporting a potential clinical application to reduce rejection by the host’s immune response following xenotransplantation.

Key words

adrenocortical cells - immune tolerance - immune regulation

# Mariya Balyura and Evgeny Gelfgat contributed equally to this work


* Proprietary


 

  • References

  • 1 Bornstein SR. Predisposing factors for adrenal insufficiency. N Engl J Med 2009; 360: 2328-2339
    CrossrefPubMedGoogle Scholar
  • 2 Andrews PA, Burnapp L, Manas D, Bradley JA, Dudley C. Summary of the British Transplantation Society/Renal Association UK Guidelines for Living Donor Kidney Transplantation. Transplantation 2012; 93: 666-673
    CrossrefPubMedGoogle Scholar
  • 3 Martin P, DiMartini A, Feng S, Brown Jr. R, Fallon M. Evaluation for Liver Transplantation in Adults: 2013 Practice Guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Hepatology 2014; 59: 1144-1165
    CrossrefPubMedGoogle Scholar
  • 4 Wagner M, Earley AK, Webster AC, Schmid CH, Balk EM, Uhlig K. Mycophenolic acid versus azathioprine as primary immunosuppression for kidney transplant recipients. Cochrane Database Syst Rev 2015; 12: CD007746
    PubMedGoogle Scholar
  • 5 Bamgbola O. Metabolic consequences of modern immunosuppressive agents in solid organ transplantation. Ther Adv Endocrinol Metab 2016; 7: 110-127
    CrossrefPubMedGoogle Scholar
  • 6 Balyura M, Gelfgat E, Ehrhart-Bornstein M, Ludwig B, Gendler Z, Barkai U, Zimerman B, Rotem A, Block NL, Schally AV, Bornstein SR. Transplantation of bovine adrenocortical cells encapsulated in alginate. Proc Natl Acad Sci U S A 2015; 112: 2527-2532
    CrossrefPubMedGoogle Scholar
  • 7 Shainer R, Azar Y, Almogi-Hazan O, Bringer R, Compton SR, Paidas MJ, Barnea ER, Or R. Immune regulation and oxidative stress reduction by preimplantation factor following syngeneic or allogeneic bone marrow transplantation. Conf Papers Med 2013; 1-8
    PubMedGoogle Scholar
  • 8 Stamatkin CW, Roussev RG, Stout M, Absalon-Medina V, Ramu S, Goodman C, Coulam CB, Gilbert RO, Godke RA, Barnea ER. PreImplantation Factor (PIF) correlates with early mammalian embryo development-bovine and murine models. Reprod Biol Endocrinol 2011; 9: 63
    CrossrefPubMedGoogle Scholar
  • 9 Ramu S, Stamatkin C, Timms L, Ruble M, Roussev RG, Barnea ER. PreImplantation factor (PIF) detection in maternal circulation in early pregnancy correlates with live birth (bovine model). Reprod Biol Endocrinol 2013; 11: 105
    CrossrefPubMedGoogle Scholar
  • 10 Duzyj CM, Paidas MJ, Jebailey L, Huang JS, Barnea ER. PreImplantation Factor (PIF*) promotes embryotrophic and neuroprotective decidual genes: effect negated by epidermal growth factor. J Neurodev Disord 2014; 6: 36
    CrossrefPubMedGoogle Scholar
  • 11 Barnea ER, Vialard F, Moindjie H, Ornaghi S, Dieudonne MN, Paidas MJ. PreImplantation Factor (PIF*) endogenously prevents preeclampsia: Promotes trophoblast invasion and reduces oxidative stress. J Reprod Immunol 2016; 114: 58-64
    CrossrefPubMedGoogle Scholar
  • 12 Stamatkin CW, Roussev RG, Stout M, Coulam CB, Triche E, Godke RA, Barnea ER. Preimplantation factor negates embryo toxicity and promotes embryo development in culture. Reprod Biomed Online 2011; 23: 517-524
    CrossrefPubMedGoogle Scholar
  • 13 Barnea ER, Lubman DM, Liu YH, Absalon-Medina V, Hayrabedyan S, Todorova K, Gilbert RO, Guingab J, Barder TJ. Insight into PreImplantation Factor (PIF*) mechanism for embryo protection and development: target oxidative stress and protein misfolding (PDI and HSP) through essential RIPK binding site. PLoS One 2014; 9: e100263
    CrossrefPubMedGoogle Scholar
  • 14 Goodale LF, Hayrabedran S, Todorova K, Roussev R, Ramu S, Stamatkin C, Coulam CB, Barnea ER, Gilbert RO. PreImplantation Factor (PIF) protects cultured embryos against oxidative stress: Relevance for recurrent pregnancy loss (RPL) therapy. Oncotarget 2017; 1-14
    PubMedGoogle Scholar
  • 15 Barnea ER, Kirk D, Ramu S, Rivnay B, Roussev R, Paidas MJ. PreImplantation Factor (PIF) orchestrates systemic antiinflammatory response by immune cells: Effect on peripheral blood mononuclear cells. Am J Obstet Gynecol 2012; 207: 313.e1-11
    CrossrefPubMedGoogle Scholar
  • 16 Barnea ER, Kirk D, Todorova K, McElhinney J, Hayrabedyan S, Fernández N. PIF direct immune regulation: Blocks mitogen-activated PBMCs proliferation, promotes TH2/TH1 bias, independent of Ca(2+). Immunobiology 2015; 220: 865-875
    CrossrefPubMedGoogle Scholar
  • 17 Azar Y, Shainer R, Almogi-Hazan O, Bringer R, Compton SR, Paidas MJ, Barnea ER, Or R. Preimplantation factor reduces graft-versus-host disease by regulating immune response and lowering oxidative stress (murine model). Biol Blood Marrow Transpl 2013; 19: 519-528
    CrossrefPubMedGoogle Scholar
  • 18 Paidas MJ, Krikun G, Huang SJ, Jones R, Romano M, Annunziato J, Barnea ER. A genomic and proteomic investigation of the impact of preimplantation factor on human decidual cells. Am J Obstet Gynecol 2010; 202: 459 e1-8
    CrossrefPubMedGoogle Scholar
  • 19 Lee JH, Fitzgerald JB, Dimicco MA, Grodzinsky AJ. Mechanical injury of cartilage explants causes specific time-dependent changes in chondrocyte gene expression. Arthritis Rheum 2005; 52: 2386-2395
    CrossrefPubMedGoogle Scholar
  • 20 Walczak EM, Hammer GD. Regulation of the adrenocortical stem cell niche: implications for disease. Nat Rev Endocrinol 2015; 11: 14-28
    CrossrefPubMedGoogle Scholar
  • 21 Li D, Urs AN, Allegood J, Leon A, Merrill Jr. AH, Sewer MB. Cyclic AMP-stimulated interaction between steroidogenic factor 1 and diacylglycerol kinase theta facilitates induction of CYP17. Mol Cell Biol 2007; 27: 6669-6685
    CrossrefPubMedGoogle Scholar
  • 22 Shinozaki K, Yahata H, Tanji H, Sakaguchi T, Ito H, Dohi K. Allograft transduction of IL-10 prolongs survival following orthotopic liver transplantation. Gene Ther 1999; 6: 816-822
    CrossrefPubMedGoogle Scholar
  • 23 Hanukoglu I, Gutfinger T, Haniu M, Shively JE. Isolation of a cDNA for adrenodoxin reductase (ferredoxin-NADP+ reductase). Implications for mitochondrial cytochrome P-450 systems. Eur J Biochem 1987; 169: 449-455
    CrossrefPubMedGoogle Scholar
  • 24 Barnea ER, Hayrabedyan S, Todorova K, Almogi-Hazan O, Or R, Guingab J, McElhinney J, Fernandez N, Barder T. PreImplantation factor (PIF*) regulates systemic immunity and targets protective regulatory and cytoskeleton proteins. Immunobiology 2016; 221: 778-793
    CrossrefPubMedGoogle Scholar
  • 25 Dinant S, Veteläinen RL, Florquin S, van Vliet AK, van Gulik TM. IL-10 attenuates hepatic I/R injury and promotes hepatocyte proliferation. J Surg Res 2007; 141: 176-182
    CrossrefPubMedGoogle Scholar
  • 26 Heine G, Drozdenko G, Grün JR, Chang HD, Radbruch A, Worm M. Autocrine IL-10 promotes human B-cell differentiation into IgM- or IgG-secreting plasmablasts. Eur J Immunol 2014; 44: 1615-1621
    CrossrefPubMedGoogle Scholar
  • 27 Mueller M, Schoeberlein A, Zhou J, Joerger-Messerli M, Oppliger B, Reinhart U, Bordey A, Surbek D, Barnea ER, Huang Y, Paidas M. PreImplantation Factor bolsters neuroprotection via modulating Protein Kinase A and Protein Kinase C signaling. Cell Death Differ 2015; 22: 2078-2086
    CrossrefPubMedGoogle Scholar
  • 28 Mueller M, Zhou J, Yang L, Gao Y, Wu F, Schoeberlein A, Surbek D, Barnea ER, Paidas M, Huang Y. PreImplantation factor promotes neuroprotection by targeting microRNA let-7. Proc Natl Acad Sci USA 2014; 111: 13882-13387
    CrossrefPubMedGoogle Scholar