IL-16 Induces Intestinal Inflammation via PepT1 Upregulation in a Pufferfish Model: New Insights into the Molecular Mechanism of Inflammatory Bowel Disease

Abstract

Inflammatory bowel disease (IBD) has long been a worldwide health care problem with a persistently increasing incidence. Although its clinical features have been well described, its etiology and pathogenesis remain unclear. IL-16 is a chemoattractant cytokine with various effects on cellular activities and diseases. However, the involvement of IL-16 in IBD remains poorly understood. In this study, to our knowledge we report for the first time the mechanism by which IL-16 induces intestinal inflammation by upregulating the expression of oligopeptide transporter member 1 (PepT1) in a Tetraodon nigroviridis fish model. The dextran sodium sulfate–induced colitis model in this species revealed that IL-16 levels significantly increase accompanied by elevations in PepT1 in the colon. Moreover, the signs of colitis were dramatically attenuated by IL-16 depletion using anti–IL-16 Abs. In vivo IL-16 administration induced remarkable intestinal inflammation with typical ulcerative colitis–like features, including histologic damage, inflammatory cell infiltration, increased myeloperoxidase activity, and proinflammatory cytokines expression, which corresponded with significant PepT1 upregulation in the colon. The IL-16–induced PepT1 expression and its upregulated fMLF transport were also demonstrated in vitro. To our knowledge, our study provides the first evidence of the connection between IL-16 and PepT1, which provides new insights into the molecular mechanism underlying IBD development. Additionally, this study suggests that fish species are an attractive model for studying IBD. By providing a better understanding of IL-16 biology from fish to mammals, this study should aid the development of IL-16–based therapies for IBD.

Chemokine and cytokine levels in inflammatory bowel disease patients

“…It has been shown that IL-16 expression increase in IBD patients as compared to healthy donors [24]. Further, IL-16 exerts a strong chemoattractant activity on CD4 + cells and induces intestinal inflammation through PepT1 upregulation [43]. TNF-α is increased in the colon tissue of IBD patients [44].…”

Colonic miRNA Expression/Secretion, Regulated by Intestinal Epithelial PepT1, Plays an Important Role in Cell-to-Cell Communication during Colitis

“…However, colonic PepT1 expression is enhanced under conditions of chronic inflammation such as Inflammatory Bowel Disease (IBD) [4], [6], [7]. Recently, a polymorphism of the hPepT1 gene has been shown to be associated with IBD susceptibility, indicating a direct involvement of this transporter in IBD [8].…”

Gleaning Insights from Fecal Microbiota Transplantation and Probiotic Studies for the Rational Design of Combination Microbial Therapies

“…Despite the abundance of pro-and anti-inflammatory cytokines, such as IL-12, TNF-␣, IL-1␤, IL-16, and transforming growth factor ␤ (TGF-␤), that can be found in UC patients (234,237,(239)(240)(241), UC has traditionally been considered a CD4 ϩ T helper cell type 2 (Th2) disease (242,243). This view stemmed from the observation that increased levels of Th2-associated cytokines, including IL-5 and IL-13, can be measured in UC patients and experimental colitis models (239,243,244).…”