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Mesenchymal stem cells (MSCs) are potent immunoregulators and have shown clinical utility in suppressing immunity. MSC function is modulated by cytokines, since inflammatory cytokines, such as interferon‐γ (IFNγ) concomitant with tumor necrosis factor‐α (TNFα), induce their immunoregulatory capability. Here, we show that IFNγ and TNFα act synergistically to induce high levels of expression of interleukin‐6 (IL‐6) and several other immune‐related molecules in MSCs in vitro. We further found that, while either IFNγ or TNFα alone induced minor expression of C/EBPβ in MSCs, this transcription factor was dramatically upregulated when these cytokines were added together. A causal relationship between C/EBPβ upregulation and IL‐6 expression was demonstrated by small interfering RNA knockdown of C/EBPβ. C/EBPβ knockdown also inhibited the synergistic expression of CXCL1, inducible nitric oxide synthase, and CCL5 in response to concomitant IFNγ and TNFα. We conclude that C/EBPβ is a key transcription factor in synergistic gene upregulation by IFNγ and TNFα. Importantly, C/EBPβ similarly mediated synergistic gene induction in response to IFNγ accompanied by IL‐1β or lipopolysaccharide, suggesting that synergy between IFNγ and other stimuli share C/EBPβ as common mechanism. Furthermore, while STAT1 is critical in IFNγ signaling, we found that STAT1 knockdown in MSCs did not affect C/EBPβ expression or the synergistic induction of IL‐6 and CXCL1 by IFNγ and TNFα. Thus, C/EBPβ is not regulated by STAT1. These results demonstrate the importance of cytokine interactions in MSC immunobiology, a better understanding of which will allow improved clinical application of these cells. S TEM CELLS  2009;27:942–948

C/EBPβ Mediates Synergistic Upregulation of Gene Expression by Interferon‐γ and Tumor Necrosis Factor‐α in Bone Marrow‐Derived Mesenchymal Stem Cells