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

Department of Internal Medicine, University Tor Vergata of Rome, Rome, Italy.
Mucosal Immunology (Impact Factor: 7.37). 10/2010; 4(2):239-244. DOI: 10.1038/mi.2010.68


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-α (TNF-α), but not interferon-γ (IFN-γ) or IL-21, reduced IL-25 synthesis. Consistently, IL-25 production was enhanced by anti-TNF-α both in vitro and in vivo. Upregulation of IL-25 was also seen in normal colonic explants stimulated with transforming growth factor-β1 (TGF-β1). As in IBD, TGF-β1 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-α and TGF-β1 in the human gut.

Download full-text


Available from: Livia Biancone, Feb 14, 2015
6 Reads
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In the gut of patients with inflammatory bowel disease (IBD), immune and nonimmune cells produce large amounts of cytokines that drive the inflammatory process leading to the tissue damage. Cytokine blockers, such as anti-tumor necrosis factor alpha (TNF-α), have been used with some success in IBD. However, not all patients respond, and the therapeutic effects wane with time, demonstrating the need for more effective and long-lasting antiinflammatory strategies. A key question is whether neutralizing other proinflammatory cytokines such as interleukin (IL)-12, IL-21, IL-27, or IL-33 will lead to a better clinical response than with anti-TNF-α antibodies. Equally, we now know that IBD-related inflammation is marked by defective production/activity of antiinflammatory cytokines, and there are strategies to correct these defects. An alternative approach is to try to target individual therapies to individual patients, to improve clinical efficacy in subsets of patients, but this has proven difficult. Here we try to evaluate the potential of each of these choices. (Inflamm Bowel Dis 2012;).
    Inflammatory Bowel Diseases 11/2012; 18(11):2180-9. DOI:10.1002/ibd.22967 · 4.46 Impact Factor
  • Source
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Recently, we demonstrated a novel role for gastrointestinal mast cells (MCs) in the early events that lead to the generation of Th2 immunity to helminth infection.11. Hepworth MR, Daniłowicz-Luebert E, Rausch S, Metz M, Klotz C, Maurer M, et al. Mast cells orchestrate type 2 immunity to helminths through regulation of tissue-derived cytokines. Proc Natl Acad Sci U S A 2012; 109:6644 - 9;; PMID: 22493240 [CrossRef]View all references Mice lacking MCs (KitW/KitW-v and KitW-Sh) showed a significant inhibition of Th2 cell priming following infection with the parasitic helminth Heligmosomoides polygyrus bakeri (Hp). We showed that MCs degranulate during the early stages of infection when the helminth larvae invade the small intestinal tissue. Furthermore, MC degranulation was required for the enhanced expression and production of the tissue-derived cytokines IL-25, IL-33 and TSLP, which are required for the optimal orchestration and priming of type 2 immunity. In this addendum we aim to address several questions raised by our findings — in particular, the mechanisms through which MCs may recognize helminth exposure in the early stages of infection and by which they may enhance expression of critical tissue cytokines thus, enabling Th2 priming. Furthermore, we will discuss these findings in the context of recently described novel innate immune cells, such as type 2 hematopoietic progenitors and type 2 innate lymphoid cells.
    Gut Microbes 09/2012; 3(5):476-81. DOI:10.4161/gmic.21507
Show more