Credit: S.Bradbrook/NPG

A failure to resolve inflammation in a timely manner can have serious consequences for health. As such there are numerous molecular 'brakes' that can be applied to inflammatory responses. In a recent Nature paper, a new role is described for the methylcytosine dioxygenase TET2 in specifically repressing transcription of the pro-inflammatory cytokine interleukin-6 (IL-6) and ensuring timely termination of inflammation.

Deficiency of TET2 in mouse or human myeloid cells did not affect the rapid induction of IL-6 expression that occurs within 4 hours of stimulation with lipopolysaccharide (LPS). However, TET2-deficient cells failed to downregulate IL-6 expression at the late phase of the LPS response (after 8 hours). TET2 was also found to repress the transcription of other LPS-induced genes (including Rsad2, Cmpk2 and Ifit2) that have the same dynamic transcription patterns as Il6, but it had no effect on transcription of tumour necrosis factor (Tnf).

The biological significance of TET2-mediated repression of inflammation was assessed in mice with a myeloid cell-specific deletion of Tet2 given a systemic challenge with LPS. These mice produced much more IL-6, especially at the late phase, and showed more severe lung damage and diffuse inflammation than wild-type mice. Tet2-deficient mice were also more susceptible to dextran sulfate sodium-induced colitis, showing exacerbated colon inflammation and tissue damage compared with control mice.

During the late phase of LPS stimulation, higher levels of TET2 bound to the Il6 promoter. Moreover, co-immunoprecipitation and mass spectrometry studies identified several transcription factors that associated with TET2 in myeloid cells. Of these binding partners, NF-κB inhibitor-ζ (IκBζ), which is known to target the Il6 promoter during the LPS response, was shown to mediate specific targeting of TET2 to the Il6 promoter. In addition, TET2 was found to associate with histone deacetylase 1 (HDAC1) and HDAC2. In the presence of inhibitors of HDACs, high levels of Il6, but not Tnf, transcription were maintained during the late phase of the LPS response, suggesting that loss of histone acetylation is important for repressing Il6 transcription.

TET2 ... selectively mediates the repression of Il6 transcription through HDACs

So, this study shows that TET2, independent of its established roles in DNA methylation and hydroxymethylation, selectively mediates the repression of Il6 transcription through HDACs that erase histone acetylation during inflammation resolution in myeloid cells. Importantly, it implies that repression at the chromatin level, and not termination of Toll-like receptor signalling, is a key mechanism for regulating inflammatory cytokine expression.