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  • br Conclusions br Introduction G


    Introduction G protein-coupled receptors (GPRs) share common structural motifs, including seven transmembrane helices, and the ability to activate heterotrimeric G proteins such as Gs, Gi, Gq and G12/13. A variety of GPR cellular functions are mediated by second messengers such as cAMP, Ca2+, inositol 1,4,5-triphosphate, and diacyl glycerol (DAG) [1], [2]. GPR35 is a member of the GPR family identified as the receptor for kynurenic acid, 2-oleoyl lysophosphatidic P005091 (2-oleoyl LPA), pamoic acid, zaprinast, and YE120 [3], [4], [5], [6], [7], [8]. GPR35 is mainly found in the immune and central nervous systems, as well as in the gastrointestinal tract, where it is highly expressed in the stomach, small intestine, and colon of humans and mice [3], [9]. By in situ hybridization, GPR35-specific signalling has also been revealed in mouse epithelial cells but not in lamina propria [3]. However, the physiological functions of GPR35 in the colonic epithelium are currently unknown. Recently, GPR35 has been clinically implicated in the onset of inflammatory bowel disease (IBD) [9]. Furthermore, a missense single nucleotide polymorphism (SNP) in the GPR35 gene has been identified in patients with ulcerative colitis, whereas GPR35 polymorphism at the 2q37 locus has been observed in Korean patients with Crohn’s disease [10], [11]. These interesting findings indicate that the functional defects of GPR35 may be related to the pathogenesis of IBD. The loss of integrity in the intestinal and colonic epithelium and inefficient mucosal repair are important factors triggering IBD onset [12]. Epithelial tissue is essential not only for maintaining mucosal homeostasis and controlling inflammation but also for wound repair in the gastrointestinal tract [13]. The migration and proliferation of epithelial cells are closely involved in physiological remodelling and wound healing following pathological insults [13], [14], [15]. The migration of neighbouring epithelial cells to the wound creates a sheet, which covers the damaged surface and is referred to as epithelial restitution [16]. Small mucosal wounds are efficiently resealed by migrating epithelial cells, whereas the repair of larger wounds requires epithelial cell proliferation, which increases the number of cells repopulating the wound, thus contributing to mucosal wound closure [13]. It was also shown that GPR35 mediates human vascular smooth muscle cell migration and endothelial cell proliferation [17]. Given that GPR35 is expressed in epithelial cells and is possibly involved in IBD pathogenesis, we hypothesized that this receptor plays a role in the physiological and pathological processes in the colonic epithelium and is associated with mucosal repair.
    Material and methods
    Discussion GPR35 is expressed in the cardiovascular, gastrointestinal, and nervous systems, and in inflammatory cells such as macrophages, mast cells, and invariant natural killer T cells [3], [7], [9], [26], [27]. In the gastrointestinal tract, GPR35 is highly expressed in the epithelium of the stomach, small intestine, and colon in humans and mice [3], [9]. In our study, we also confirmed that GPR35 was expressed by gastrointestinal epithelial cells, including colonic YAMC cells and mouse colon tissue, indicating a functional role of GPR35 in the colonic epithelium. GPR35 has been linked to several pathological conditions such as acute myocardial infarction, asthma, and pain [6], [28], [29]. In the gastrointestinal tract, GPR35 has been implicated in the onset of IBD caused by a missense SNP in the GPR35 gene [9], [10], [11]. These reports indicate that GPR35 dysfunction may be related to IBD pathogenesis, and the assessment of GPR35 roles in the physiological and pathological processes in the colon could be important for understanding molecular mechanisms underlying IBD development. In the present study, we observed that GPR35 stimulation promoted wound repair via migration (but not proliferation) of YAMC cells and ameliorated DSS-induced colitis in mice. To the best of our knowledge, this is the first study to demonstrate a functional role of GPR35 in gastrointestinal epithelial cell physiology and IBD pathogenesis. Our results are consistent with those of previous studies showing the effects of GPR35 ligands such as kynurenic acid and LPA on IBD. Thus, kynurenic acid inhibited inflammation and decreased colonic motility in trinitrobenzenesulphonic acid (TNBS)-induced colitis in rats [30], whereas LPA enhanced the migration of IEC-6 cells in vitro and ameliorated intestinal and colonic epithelial injury in a murine model [31], [32]. These findings indicate a possibility that the ameliorative effects of kynurenic acid and LPA may be mediated by the P005091 activation of GPR35.