Role of dipeptidyl peptidase IV (DP IV)-like enzymes in T lymphocyte activation: investigations in DP IV/CD26-knockout mice.

Abstract

BACKGROUND:

Dipeptidyl peptidase IV (DP IV, CD26) and DP IV-like enzymes, such as dipeptidyl peptidase II (DP II), dipeptidyl peptidase 8 (DP8), and dipeptidyl peptidase 9 (DP9), have been recognized to regulate T lymphocyte activation. Lys[Z(NO2)]-thiazolidide (LZNT) and Lys[Z(NO2)]-pyrrolidide (LZNP), non-selective inhibitors of DP IV-like activity known to target DP IV as well as DP II, DP8, and DP9, suppress T lymphocyte proliferation in vitro. Moreover, these inhibitors are capable of attenuating the severity of autoimmune diseases, such as experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis, and experimental arthritis, a model of human rheumatoid arthritis, in vivo, particularly in combination with inhibitors of aminopeptidase N (APN, CD13) enzymatic activity.

METHODS:

Here, we studied the influence of non-selective and selective inhibitors of DP IV-like enzymes on DNA synthesis in mitogen-stimulated splenocytes from wild-type C57BL/6 mice and DP IV/CD26-knockout (DP IV/CD26-KO) mice.

RESULTS:

LZNT and LZNP, the non-selective inhibitors of DP IV-like activity, suppressed the DNA synthesis in stimulated splenocytes from wild-type and DP IV/ CD26-KO mice to a comparable extent. Further, a selective inhibitor of DP8/DP9 activity was capable of suppressing DNA synthesis in mitogen-stimulated splenocytes of both wild-type and knockout mice to the same extent. In contrast, selective inhibitors of DP IV and DP II lacked this suppressive activity.

CONCLUSIONS:

Our data support the hypothesis that DP8 and/or DP9 represent additional pharmacological targets for the suppression of T cell proliferation and for anti-inflammatory therapy.

• Authors: Dirk Reinhold, Alexander Goihl, Sabine Wrenger, Annegret Reinhold, Ulrike C Kühlmann, Jürgen Faust, Klaus Neubert, Anja Thielitz, Stefan Brocke, Michael Täger, Siegfried Ansorge, Ute Bank
• Journal: Clinical chemistry and laboratory medicine (Clin Chem Lab Med) Vol. 47 Issue 3 Pg. 268-74 ( 2009) ISSN: 1434-6621 [Print] Germany
• PMID: 19676138 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Pyrrolidines
• Thiazoles
• lysyl-(Z(nitro))pyrrolidide
• lysyl-(Z(nitro))thiazolidide
• DNA
• Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
• dipeptidyl peptidase II
• Dipeptidyl Peptidase 4
• Lysine

Topics

• Animals
• Cell Proliferation (drug effects)
• DNA (biosynthesis)
• Dipeptidyl Peptidase 4 (deficiency, genetics)
• Dipeptidyl-Peptidases and Tripeptidyl-Peptidases (antagonists & inhibitors, genetics, immunology)
• Disease Models, Animal
• Lymphocyte Activation
• Lysine (analogs & derivatives, chemistry, pharmacology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Pyrrolidines (chemistry, pharmacology)
• Spleen (cytology, immunology)
• T-Lymphocytes (drug effects, immunology)
• Thiazoles (chemistry, pharmacology)