title: Human Umbilical Cord-Derived Mesenchymal Stem Cells Utilize Activin-A to Suppress Interferon-γ Production by Natural Killer Cells.
abstract: Following allogeneic hematopoietic stem cell transplantation (HSCT), interferon (IFN)-γ levels in the recipient's body can strongly influence the clinical outcome. Human umbilical cord-derived mesenchymal stem cells (UC-MSCs) are lucrative as biological tolerance-inducers in HSCT settings. Hence, we studied the molecular mechanism of how UC-MSCs influence natural killer (NK) cell-mediated IFN-γ production. Allogeneic NK cells were cultured in direct contact with UC-MSCs or cell-free supernatants from mesenchymal stem cell (MSC) cultures (MSC-conditioned media). We found that soluble factors secreted by UC-MSCs strongly suppressed interleukin (IL)-12/IL-18-induced IFN-γ production by NK cells by reducing phosphorylation of STAT4, NF-κB, as well as T-bet activity. UC-MSCs secreted considerable amounts of activin-A, which could suppress IFN-γ production by NK cells. Neutralization of activin-A in MSC-conditioned media significantly abrogated their suppressive abilities. Till date, multiple groups have reported that prostaglandin (PG)-E2 produced by MSCs can suppress NK cell functions. Indeed, we found that inhibition of PGE2 production by MSCs could also significantly restore IFN-γ production. However, the effects of activin-A and PGE2 were not cumulative. To the best of our knowledge, we are first to report the role of activin-A in MSC-mediated suppression of IFN-γ production by NK cells.
authors.affiliation: Department of Clinical Immunology and Rheumatology, Hannover Medical School , Hannover , Germany.
authors.forename: Debanjana
authors.initials: D
authors.lastname: Chatterjee
authors.affiliation: Department of Clinical Immunology and Rheumatology, Hannover Medical School , Hannover , Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Marquardt
authors.affiliation: Department of Clinical Immunology and Rheumatology, Hannover Medical School , Hannover , Germany.
authors.forename: Dejene Milkessa
authors.initials: DM
authors.lastname: Tufa
authors.affiliation: Institute of Technical Chemistry, Leibniz University of Hannover , Hannover , Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Hatlapatka
authors.affiliation: Laboratory of Biochemistry and Tumor Biology, Clinic of Obstetrics and Gynecology, Hannover Medical School , Hannover , Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Hass
authors.affiliation: Institute of Technical Chemistry, Leibniz University of Hannover , Hannover , Germany ; Department of Biotechnology, University of Natural Resources and Life Science , Vienna , Austria.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Kasper
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Medicine, Hannover Medical School , Hannover , Germany.
authors.forename: Constantin
authors.initials: C
authors.lastname: von Kaisenberg
authors.affiliation: Department of Clinical Immunology and Rheumatology, Hannover Medical School , Hannover , Germany.
authors.forename: Reinhold Ernst
authors.initials: RE
authors.lastname: Schmidt
authors.affiliation: Department of Clinical Immunology and Rheumatology, Hannover Medical School , Hannover , Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Jacobs
keywords: IFN-γ production; NK cell; T-bet; UC-MSC; activin-A; suppression