Inhibition of TGF-β Signaling by IL-15: A New Role for IL-15 in the Loss of Immune Homeostasis in Celiac Disease

摘要: Background & Aims: Interleukin (IL)-15 delivers signals that drive chronic inflammation in several diseases, including celiac disease. Smad3–transforming growth factor-beta (TGF-β) signaling is instrumental to counteract proinflammatory and maintain immune homeostasis. Our goal has been investigate why the effects of IL-15 cannot be efficiently controlled by TGF-β Methods: The impact on T cells intestinal mucosa disease patients was analyzed combining cell organ cultures, immunohistochemistry, flow cytometry, real-time polymerase chain reaction, electromobility gel shift, Western blot. Results: impaired Smad3-dependent human lymphocytes downstream from Smad3 nuclear translocation. IL-15-mediated inhibition associated with a long-lasting activation c-jun-N-terminal kinase reversed c-jun antisense oligonucleotides, consistent demonstrated inhibitory effect phospho-c-jun formation Smad3–DNA complexes. In active disease, showed TGF-β–Smad3-dependent transcriptional responses up-regulation phospho-c-jun. Anti-IL-15 antibody both downmodulated expression restored TGF-β–Smad-dependent transcription biopsies decreased interferon gamma transcription. Conclusions: Impairment TGF-β-mediated might promote sustain More generally, our data provide new rationale for potent IL-15, further support concept meaningful therapeutic target inflammatory diseases irreducible elevation IL-15.