Inhibition of CD26/Dipeptidyl Peptidase IV Enhances CCL11/Eotaxin-Mediated Recruitment of Eosinophils In Vivo

Abstract

Chemokines mediate the recruitment of leukocytes to the sites of inflammation. N-terminal truncation of chemokines by the protease dipeptidyl peptidase IV (DPPIV) potentially restricts their activity during inflammatory processes such as allergic reactions, but direct evidence in vivo is very rare. After demonstrating that N-terminal truncation of the chemokine CCL11/eotaxin by DPPIV results in a loss of CCR3-mediated intracellular calcium mobilization and CCR3 internalization in human eosinophils, we focused on the in vivo role of CCL11 and provide direct evidence for specific kinetic and rate-determining effects by DPPIV-like enzymatic activity on CCL11-mediated responses of eosinophils. Namely, it is demonstrated that i.v. administration of CCL11 in wild-type F344 rats leads to mobilization of eosinophils into the blood, peaking at 30 min. This mobilization is significantly increased in DPPIV-deficient F344 rats. Intradermal administration of CCL11 is followed by a dose-dependent recruitment of eosinophils into the skin and is significantly more effective in DPPIV-deficient F344 mutants as well as after pharmacological inhibition of DPPIV. Interestingly, CCL11 application leads to an up-regulation of DPPIV, which is not associated with negative feedback inhibition via DPPIV-cleaved CCL11(3–74). These findings demonstrate regulatory effects of DPPIV for the recruitment of eosinophils. Furthermore, they illustrate that inhibitors of DPPIV have the potential to interfere with chemokine-mediated effects in vivo including but not limited to allergy.

Dipeptidylpeptidase 4 inhibition enhances lymphocyte trafficking, improving both naturally occurring tumor immunity and immunotherapy

“…Indeed, only a few mouse chemokines have been reported to be DPP4 substrates 21,22 . As indicated above, we directly tested the ability of DPP4 to truncate an extended panel of chemokines ( Fig.…”

Bullous pemphigoid associated with dipeptidyl peptidase IV inhibitors. A case report and review of literature.

“…13 Inhibition of DPP-IV by gliptins could promote eosinophil activation in the skin by a CCL11/exotaxin-mediated mechanism. 7,14 Eosinophil activation is known to contribute significantly to blister formation in bullous pemphigoid. 1,2,14 Decreased levels of DPP-IV enzyme has also been associated with increased levels of transforming growth factor beta-1 (TGF beta 1) in T cells leading to its extracellular secretion.…”

Analgesic and anti-inflammatory effectiveness of sitagliptin and vildagliptin in mice

“…Further studies are needed to support the suggestion 32 that the utilization of these beneficial effects of gliptins may be considered in the treatment of Type 2 diabetic 33 patients. 34 © 2014 Published by Elsevier B.V. …”