TET1 is a negative transcriptional regulator of IL-1β in the THP-1 cell line

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TET1 is a member of the recently identified family of epigenetic regulators, TET1-3 which catalyze the enzymatic conversion of the methyl mark on cytosine (methylcytosine, mC) to the hydroxymethyl mark (hmC). The functions of hmC are required for stem cell maintenance and for controlling differentiation and reprogramming. So far, no roles for TET proteins have been identified in cells of the immune system. Here we show that TET1 is a negative regulator of IL-1β transcription following an inflammatory stimulus and negatively modulates IL-1β secretion in THP-1 cells. In addition, TET1 expression is regulated during inflammation both in THP-1 and in primary dendritic cells. Importantly, other highly induced pro-inflammatory genes are also regulated by TET1, including cytokines, chemokines and adhesion molecules. The other member of the TET family with known roles in stem cell regulation, TET2, is also regulated in THP-1 cells following the inflammatory stimulus and may also participate in IL-1β regulation, according to our observations. Our results suggest a TET1-dependent anti-inflammatory pathway, which may include TET2. In particular, IL-1β transcriptional regulation is likely to depend on TET1-regulated chromatin domains. This work highlights the contribution of epigenetic mechanisms to the efficient organization of inflammatory responses.

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