TNF-α and IL-1β sensitize human MSC for IFN-γ signaling and enhance neutrophil recruitment

During inflammatory processes, tissue environmental cues are influencing the immunoregulatory properties of tissue-resident mesenchymal stem/stromal cells (MSC). In this study, we elucidated one of the molecular and cellular responses of human MSC exposed to combinations of inflammatory cytokines. We showed that during multi-cytokine priming by TNF-alpha, IL-1 beta, and IFN-gamma, IL-1 beta further augmented the well-established immunoregulatory activity induced by TNF-alpha/IFN-gamma. On the molecular level, TNF-alpha and IL-1 beta enhanced the expression of IFN-gamma receptor (IFN-gamma R) via NF 'kappa-light-chain-enhancer' of activated B-cells (NF-kappa Beta) signaling. In turn, enhanced responsiveness to IFN-gamma stimulation activated STAT5 and p38-MAPK signaling. This molecular feedback resulted in an increased IL-8 release and augmented recruitment of polymorphonuclear granulocytes (PMN). Our study suggests the possibility that responses of MSC to multi-cytokine priming regimens may be exploited therapeutically to fine-tune inflammatory activity in tissues. This study elucidates molecular mechanisms underlying the immunological priming of mesenchymal stromal cells (MSC) and their interaction with neutrophils.