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Dual Inhibition of Dipeptidyl Peptidase IV and Aminopeptidase N Suppresses Inflammatory Immune Responses
Author(s) -
REINHOLD DIRK,
BITON ALIZA,
GOIHL ALEXANDER,
PIEPER STEFANIE,
LENDECKEL UWE,
FAUST JÜRGEN,
NEUBERT KLAUS,
BANK UTE,
TÄGER MICHAEL,
ANSORGE SIEGFRIED,
BROCKE STEFAN
Publication year - 2007
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1423.042
Subject(s) - dipeptidyl peptidase , experimental autoimmune encephalomyelitis , in vivo , aminopeptidase , chemistry , immune system , in vitro , t cell , dipeptidyl peptidase 4 , pharmacology , cytokine , cancer research , enzyme , biochemistry , biology , immunology , endocrinology , leucine , microbiology and biotechnology , amino acid , diabetes mellitus , type 2 diabetes
Abstract : The ectopeptidases dipeptidyl peptidase IV (DP IV, CD26) and aminopeptidase N (APN, CD13) are known to regulate T cell activation. Since selective inhibitors of DP IV and APN suppress DNA synthesis and cytokine production of stimulated T cells in a TGF‐β1‐dependent manner, we tested whether combined application of DP IV and APN inhibitors enhances this immunomodulatory effect. The results show that simultaneous application of DP IV and APN inhibitors significantly suppressed DNA synthesis in mitogen‐ or anti‐CD3‐stimulated human T cells in vitro when compared to the use of a single DP IV or APN inhibitor. Moreover, the combined action of DP IV and APN inhibitors markedly increased TGF‐β1 production associated with the observed immunosuppressive effects. In vivo , targeting both DP IV and APN led to a potent treatment of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (MS). This review summarizes the evidence for the role of both enzymes in T cell activation in vitro and in vivo and provides a rationale for using combined and dual peptidase inhibitors to treat autoimmune diseases like MS.