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VASCULAR BIOLOGY

Lacking cytokine production in ES cells and ES-cell-derived vascular cells stimulated by TNF- is rescued by HDAC inhibitor trichostatin A

Cardiovascular Division, King's College London, London, United Kingdom

Submitted 12 April 2007 ; accepted in final form 11 July 2007

Inflammation and TNF- signaling play a central role in most of the pathological conditions where cell transplantation could be applied. As shown by initial experiments, embryonic stem (ES) cells and ES-cell derived vascular cells express very low levels of TNF- receptor I (TNFRp55) and thus do not induce cytokine expression in response to TNF- stimulation. Transient transfection analysis of wild-type or deletion variants of the TNFRp55 gene promoter showed a strong activity for a 250-bp fragment in the upstream region of the gene. This activity was abolished by mutations targeting the Sp1/Sp3 or AP1 binding sites. Moreover, treatment with trichostatin A (TSA) led to a pronounced increase in TNFRp55 mRNA and promoter activity. Overexpression of Sp1 or c-fos further enhanced the TSA-induced luciferase activity, and this response was attenuated by Sp3 or c-jun coexpression. Additional experiments revealed that TSA did not affect the Sp1/Sp3 ratio but caused transcriptional activation of the c-fos gene. Thus, we provide the first evidence that ES and ES-cell-derived vascular cells lack cytokine expression in response to TNF- stimulation due to low levels of c-fos and transcriptional activation of Sp1 that can be regulated by inhibition of histone deacetylase activity.

inflammation; TNFRp55; c-fos; Sp1

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