Role of Dipeptidyl Peptidase IV/CD26 in Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) comprises two main chronic pathologies of the gastrointestinal tract (GIT): ulcerative colitis (UC) and Crohn’s disease (CD), both characterized by alternating phases of active inflammation and clinical remission with different complications and extraintestinal manifestations. The ethiopathogenesis of IBD has still not been elucidated, but it has been suggested that inflammatory processes emerge in genetically susceptible individuals as a result of an irregular, over-expressed immunological reaction to some undefined food antigens or some other agents of microbial origin. Given the complexity of etiological factors in human IBD, a lot of current knowledge regarding IBD pathogenesis has arisen from the study of various animal models. Although no ideal model of IBD has been accomplished so far, they resemble different important clinical, histopathological and immunological aspects of human IBD. Chemically induced murine models by oral administration of dextran sodium sulfate (DSS) and intrarectal aplication of 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) are the most commonly used due to their onset and duration of colonic inflammation which is immediate, reproducible and shares a lot of similarities with human IBD. TNBS-induced colitis is one of the most accepted and used Crohn-like disease while DSS model is clinically and histologically similar to human ulcerative colitis. These models, together with other animal models of IBD, have given insight in different processes at the molecular level and have revealed the importance of different molecules involved in IBD etiology, representing therefore essential tools in investigating different mechanisms underlying acute or chronic inflammation in the IBD. Growing body of knowledge proposes proteases as key factors in the occurrence of inflammatory processes due to their ability to metabolize different biologically active molecules implicated in maintaining the integrity of mucosal barrier (8). Dipeptidyl-peptidase IV, known also as CD26 molecule (DPP IV/CD26) is one of them (9). DPP IV/CD26 is also T-cell differentiation antigen, expressed on various cell types, having numerous functions in a variety of biological processes, as well as immunological mechanisms. It is also present in a soluble form circulating in body fluids in living organisms with specific peptidase function having unique features in substrate processing: it cleaves dipeptides from the N terminus of polypeptides having proline or alanin at the penultimate position. Since Xaa-Pro peptides are not easily metabolized by other proteases, the action of DPP IV/CD26 is an essential step in the degradation of many polypeptides. Numerous biologically important cytokines, chemokines and neuropeptides with potential and/or confirmed role in IBD ethiopathogenesis are effective DPP IV/CD26 substrates. Previous studies including patients affected with IBD showed a correlation between disease severity and serum DPP IV/CD26 activity. Furthermore, a potential role of DPP IV/CD26 in the pathogenesis of IBD, given its involvement in immune regulations via its expression on immune cells and capability to cleave biologically active molecules has been proposed. Additionally, DPP IV/CD26 inhibitors have been pointed out as therapeutic agents in ameliorating inflammatory processes in immunologically mediated diseases such as IBD. Given the potential role of DPP IV/CD26 and possible involvement in the pathogenesis of IBD, the aim of this study was to investigate and review does it and in which manner the deficiency of DPP IV/CD26 affect the neuroimmune response during development, progression and resolution of inflammatory events in two models of IBD in mice.