Regulation of Expression and Function of Dipeptidyl Peptidase 4 (DP4), DP8/9, and DP10 in Allergic Responses of the Lung in Rats

Abstract

S U M M A R Y The expression of dipeptidyl peptidase 4 (DP4, CD26) affects T-cell recruitment to lungs in an experimental rat asthma model. Furthermore, the gene of the structural homologous DP10 represents a susceptibility locus for asthma in humans, and the functional homologous DP8/9 are expressed in human leukocytes. Thus, although several mechanisms may account for a role of DP4-like peptidases in asthma, detailed information on their anatomical sites of expression and function in lungs is lacking. Therefore, bronchi and lung parenchyma were evaluated using immunohistochemistry and histochemical/enzymatic activity assays, as well as quantitative real-time PCR for this family of peptidases in naïve and asthmatic rat lungs derived from wild-type F344 and DP4-deficient F344 rat strains. Surprisingly, results show not only that the induction of experimental asthma increases DP4 enzymatic activity in the bronchoalveolar lavage fluid and parenchyma, but also that DP8/9 enzymatic activity is regulated and, as well as the expression of DP10, primarily found in the bronchial epithelium of the airways. This is the first report showing a differential and sitespecific DP4-like expression and function in the lungs, suggesting a pathophysiologically significant role in asthma. (J Histochem Cytochem 56:147-155, 2008)

Unravelling the immunological roles of dipeptidyl peptidase 4 (DPP4) activity and/or structure homologue (DASH) proteins

“…The human gene localization is 7q36.1-q36.2. DPL1 is associated with amyotrophic lateral sclerosis, familial idiopathic ventricular fibrillation, spinal muscular atrophy and neuroleptic-induced tardive dyskinesia, whereas DPL2 is linked with asthma [44,61,[64][65][66][67][68]. The crystal structures of DPL1 and DPL2, respectively, resemble that of DPP4 [63,69].…”

“…So far, one cannot differentiate between DPP8 and DPP9 enzymatic activity due to the lack of selective inhibitors; however, DPP8/DPP9 activity could be detected in human leucocytes, rat brain, lung and testis, bovine testis, murine brain, organs of the immune system such as thymus, spleen, lymph nodes and peripheral blood mononuclear cells (PBMC), testis, skeletal and uterine muscles as well as colon [12,35,36,[44][45][46][47]. Nevertheless, brain and testis have been the only organs in which DPP8/DPP9 activities precede over DPP4 activity [12,35,45,46].…”

“…However, the suggested cytotoxicity of DPP8/DPP9 inhibition is currently discussed controversially [52][53][54][55][56]. An increase of DPP8/DPP9 activity has been associated with asthma [44]. Extra-enzymatic functions of DPP8/DPP9 include cell adhesion, migration and apoptosis [57].…”

Enzyme Activity and Immunohistochemical Localization of Dipeptidyl Peptidase 8 and 9 in Male Reproductive Tissues

“…Also, human leukocytes contained DPP8/9 activity (Maes et al 2007a). DPP8 and DPP9 were upregulated in the bronchi after induction of experimental asthma in the rat (Schade et al 2008). The precise functions of these enzymes in vivo are still unknown.…”

The amino terminus extension in the long dipeptidyl peptidase 9 isoform contains a nuclear localization signal targeting the active peptidase to the nucleus

“…For example, DPP9 protein levels are increased upon differentiation of monocytes to macrophages [24]. Increases in mRNa levels of DPP9 are detected in inflamed lungs and chronic lymphocytic leukemia [32,33].…”