Interleukin-25 production is differently regulated by TNF-α and TGF-β1 in the human gut

An altered balance between effector and regulatory factors is supposed to sustain the tissue-damaging immune response in inflammatory bowel disease (IBD). We have recently shown that in IBD, there is a defective synthesis of the counter-regulatory cytokine, interleukin (IL)-25. In this study we investigated factors that control IL-25 production in the gut. IBD patients produced less IL-25 when compared with normal controls. Stimulation of normal intestinal explants with tumor necrosis factor-alpha (TNF-alpha), but not interferon-gamma (IFN-gamma) or IL-21, reduced IL-25 synthesis. Consistently, IL-25 production was enhanced by anti-TNF-alpha both in vitro and in vivo. Upregulation of IL-25 was also seen in normal colonic explants stimulated with transforming growth factor-beta 1 (TGF-beta 1). As in IBD, TGF-beta 1 activity is abrogated by Smad7, we next assessed whether inhibition of Smad7 with an antisense oligonucleotide enhanced IL-25 expression. Knockdown of Smad7 was accompanied by an increase in IL-25 production. Data show that IL-25 production is differently regulated by TNF-alpha and TGF-beta 1 in the human gut.