Keywords: Dipeptidyl peptidase, CD26, Lymphocytes, Veliparib ABT-888 Liver fibrosis, Biliary fibrosis INTRODUCTION The four enzyme members of the dipeptidyl peptidase (DPP) 4 gene family, DPP4, fibroblast activation protein (FAP), DPP8 and DPP9, have attracted considerable research interest in recent years since DPP4 inhibitors became a successful therapy for type 2 diabetes[1,2]. FAP is a potential cancer therapeutic target[2,3]. DPP4, the most well characterized family member, has ubiquitous cell surface and extracellular expression[2,4-7]. DPP8 and DPP9 are the most recently discovered members of the DPP4 gene family[8-11]. DPP4, DPP8 and DPP9 are ubiquitously expressed cytosolic enzymes with DPP4-like activity[8,11,12].

They are expressed by major epithelial organs including liver, colon, small intestine, stomach, lung, skin, tongue, kidney, testis and the lymphoid cells of lymph node, blood, thymus, and spleen[13]. The biological functions of DPP8 and DPP9 are largely uncharacterized. DPP4 is also known as CD26 and has important roles in the immune system. It is a costimulatory molecule in T cell activation and proliferation and is critical in the development of T helper 1 responses to foreign antigens. It is expressed at detectable levels by some resting T cells but the cell surface expression increases 5-10 fold following stimulation with antigen or anti-CD3+ interleukin-2 or with mitogens such as phytohaemagglutinin[14-19]. However, the costimulatory role of DPP4/CD26 is mediated by extra-enzymatic activities[20-22].

Hence, some of the immunological effects observed in early DPP4 inhibitor studies are now thought to be due to off-target non-selective inhibition of DPP8 and DPP9[2,23,24]. In support of this viewpoint, there is some evidence that DPP8 and DPP9 are functionally significant in the immune system. Their mRNA levels are elevated in activated human leukocytes[25,26]. An inhibitor of DPP8 and DPP9 attenuates proliferation in in vitro models of human T-cell activation[23]. An inhibitor selective for DPP8 and DPP9 vs related proteases can suppress DNA synthesis in mitogen-stimulated splenocytes from both wildtype DPP4+/+ and DPP4-/- gene knockout (gko) mice[27]. Moreover, DPP8 and DPP9 Drug_discovery have been implicated in hematopoiesis and in inflammatory diseases including arthritis[2,28,29]. Most importantly, DPP8 and DPP9 are involved in processing and degradation of peptides involved in antigen presentation by Major histocompatibility complex class I[30]. Inflammatory and immune responses are important in liver injury. Improved understanding of immune response, inflammation and fibrogenic progression is needed to advance the understanding of liver disorders. DPP8 and DPP9 are expressed in hepatocytes and lymphocytes of human cirrhotic liver[13].