Journal
STEM CELLS
Volume 27, Issue 4, Pages 942-948Publisher
WILEY
DOI: 10.1002/stem.22
Keywords
C/EBP beta; Mesenchymal stem cells; IFN-gamma; TNF
Categories
Funding
- New Jersey Commission on Science and Technology [NJCST-2042-014-84]
- USPHS [AI057596]
- National Space Biomedical Research Institute [IIH00405]
- National Aeronautics and Space Administration through Cooperative Agreement [NCC 9-58]
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [P01AI057596] Funding Source: NIH RePORTER
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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 in. ammatory cytokines, such as interferon-gamma (IFN gamma) concomitant with tumor necrosis factor-alpha (TNF alpha), induce their immunoregulatory capability. Here, we show that IFN gamma and TNF alpha 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 IFN gamma or TNF alpha alone induced minor expression of C/EBP beta in MSCs, this transcription factor was dramatically upregulated when these cytokines were added together. A causal relationship between C/EBP beta upregulation and IL-6 expression was demonstrated by small interfering RNA knockdown of C/EBP beta. C/EBP beta knockdown also inhibited the synergistic expression of CXCL1, inducible nitric oxide synthase, and CCL5 in response to concomitant IFN gamma and TNF alpha. We conclude that C/EBP beta is a key transcription factor in synergistic gene upregulation by IFN gamma and TNF alpha. Importantly, C/EBP beta similarly mediated synergistic gene induction in response to IFN gamma accompanied by IL-1 beta or lipopolysaccharide, suggesting that synergy between IFN gamma and other stimuli share C/EBP beta as common mechanism. Furthermore, while STAT1 is critical in IFN gamma signaling, we found that STAT1 knockdown in MSCs did not affect C/EBP beta expression or the synergistic induction of IL-6 and CXCL1 by IFN gamma and TNF alpha. Thus, C/EBP beta 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. STEM CELLS 2009;27:942-948
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