Human Umbilical Cord-Derived Mesenchymal Stem Cells Utilize Activin-A to Suppress Interferon-? Production by Natural Killer Cells.

ABSTRACT: Following allogeneic hematopoietic stem cell transplantation (HSCT), interferon (IFN)-? 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-? 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-? production by NK cells by reducing phosphorylation of STAT4, NF-?B, as well as T-bet activity. UC-MSCs secreted considerable amounts of activin-A, which could suppress IFN-? 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-? 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-? production by NK cells.

SUBMITTER: Chatterjee D 

PROVIDER: S-EPMC4278046 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature