Research ArticleImmunology

The intracellular pyrimidine 5′-nucleotidase NT5C3A is a negative epigenetic factor in interferon and cytokine signaling

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Science Signaling  20 Feb 2018:
Vol. 11, Issue 518, eaal2434
DOI: 10.1126/scisignal.aal2434

Suppressing inflammation

Inflammatory cytokines and chemokines, such as tumor necrosis factor (TNF) and interleukin-8 (IL-8), are important for effective immune responses; however, feedback mechanisms that inhibit the production of such factors are critical to prevent tissue damage. Al-Haj and Khabar found that the gene encoding the nucleotidase NT5C3A was induced in a type I interferon (IFN)–dependent manner in many cell types. Whereas knockdown of NT5C3A enhanced inflammatory cytokine production, overexpression of the enzyme enhanced the activity of the histone deacetylases SIRT1 and SIRT6, which in turn acted on histone proteins to reduce the expression of Il8, an NF-κB target gene. Together, these data suggest that NT5C3A mediates feedback inhibition of proinflammatory cytokine production by acting epigenetically to block NF-κB signaling output.