Survey The role of IL-15 in gastrointestinal diseases: A bridge between innate and adaptive immune response Danilo Pagliari a , Rossella Cianci a , Simona Frosali a , Raffaele Landolfi a , Giovanni Cammarota a , Estelle E. Newton b , Franco Pandolfi a, * a Institute of Internal Medicine, Catholic University of the Sacred Heart, Rome, Italy b CytoCure LLC, Beverly, MA, USA Contents 1. The biology of IL-15: a cytokine of IL-2 cytokine family . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000 2. The role of IL-15 in the intestinal mucosal barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000 3. The pleiotropic functions of IL-15 in human physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000 3.1. Physiological functions of IL-15 in innate immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000 3.2. Physiological functions of IL-15 in adaptive immunity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000 3.3. Role of IL-15 in modulation of enterocyte apoptosis: does IL-15 mediate gut epithelium damage or gut epithelium homeostasis?. 000 4. The pleiotropic functions of IL-15 in human gastrointestinal pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000 4.1. The role of IL-15 in the pathogenesis of Inflammatory Bowel Diseases (IBDs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000 4.2. The role of IL-15 in the pathogenesis of Celiac Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000 4.3. The role of IL-15 in the pathogenesis of Refractory Celiac Disease (RCD) and Enteropathy Associated T-cell Lymphoma (EATL) . . . 000 4.4. The role of IL-15 in colorectal cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000 5. The involvement of IL-15 in the composition of the gastrointestinal mucosal ‘immunological niche’: modulation of immune response as a potential target of biological therapeutical approaches. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000 Cytokine & Growth Factor Reviews xxx (2013) xxx–xxx A R T I C L E I N F O Article history: Available online xxx Keywords: IL-15 Immunological niche Celiac Disease Inflammatory Bowel Diseases Colorectal cancer A B S T R A C T IL-15 is a member of the IL-2 family of cytokines whose signaling pathways are a bridge between innate and adaptive immune response. IL-15 is part of the intestinal mucosal barrier, and functions to modulate gut homeostasis. IL-15 has pivotal roles in the control of development, proliferation and survival of both innate and adaptive immune cells. IL-15 becomes up-regulated in the inflamed tissue of intestinal inflammatory disease, such as IBD, Celiac Disease and related complications. Indeed, several studies have reported that IL-15 may participate to the pathogenesis of these diseases. Furthermore, although IL-15 seems to be responsible for inflammation and autoimmunity, it also may increase the immune response against cancer. For these reasons, we decided to study the intestinal mucosa as an ‘immunological niche’, in which immune response, inflammation and local homeostasis are modulated. Understanding the role of the IL-15/IL-15R system will provide a scientific basis for the development of new approaches that use IL-15 for immunotherapy of autoimmune diseases and malignancies. Indeed, a better understanding of the complexity of the mucosal immune system will contribute to the general understanding of immuno-pathology, which could lead to new therapeutical tools for widespread immuno-mediated diseases. ß 2013 Elsevier Ltd. All rights reserved. * Corresponding author at: Institute of Internal Medicine, Catholic University of the Sacred Heart, Largo A. Gemelli 8, 00168 Rome, Italy. Tel.: +39 06 30155671; fax: +39 06 35502775. E-mail address: pandolfi@rm.unicatt.it (F. Pandolfi). G Model CGFR-735; No. of Pages 12 Please cite this article in press as: Pagliari D, et al. The role of IL-15 in gastrointestinal diseases: A bridge between innate and adaptive immune response. Cytokine Growth Factor Rev (2013), http://dx.doi.org/10.1016/j.cytogfr.2013.05.004 Contents lists available at SciVerse ScienceDirect Cytokine & Growth Factor Reviews jo ur n al ho mep ag e: www .elsevier .c om /loc ate/c yto g fr 1359-6101/$ – see front matter ß 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.cytogfr.2013.05.004