Inhibition of CD26/dipeptidyl CCL11/eotaxin-mediated recruitment peptidase IV enhances of eosinophils in vivo

被引:97
作者
Forssmann, Ulf [2 ]
Stoetzer, Carsten [3 ]
Stephan, Michael [3 ]
Kruschinski, Carsten [3 ]
Skripuletz, Thomas [3 ]
Schade, Jutta [3 ]
Schmiedl, Andreas [3 ]
Pabst, Reinhard [3 ]
Wagner, Leona [4 ]
Hoffmann, Torsten [4 ]
Kehlen, Astrid [4 ]
Escher, Sylvia E. [2 ]
Forssmann, Wolf-Georg [2 ]
Elsner, Joern [5 ]
von Hoersten, Stephan [1 ,3 ]
机构
[1] Univ Erlangen Nurnberg, Franz Penzoldt Ctr, D-91056 Erlangen, Germany
[2] Hannover Med Sch, Clin Immunol & Rheumatol, D-3000 Hannover, Germany
[3] Hannover Med Sch, Inst Funct & Appl Anat, D-3000 Hannover, Germany
[4] Probiodrug AG, Halle, Germany
[5] Fachklin Bad Bentheim, Dept Dermatol & Allergol, Bad Bentheim, Germany
关键词
D O I
10.4049/jimmunol.181.2.1120
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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-Iike 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.
引用
收藏
页码:1120 / 1127
页数:8
相关论文
共 42 条
[1]   Vildagliptin:: an inhibitor of dipeptidyl peptidase-4 with antidiabetic properties [J].
Ahrén, B .
EXPERT OPINION ON INVESTIGATIONAL DRUGS, 2006, 15 (04) :431-442
[2]   Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes [J].
Ahrén, B ;
Gomis, R ;
Standl, E ;
Mills, D ;
Schweizer, A .
DIABETES CARE, 2004, 27 (12) :2874-2880
[3]   Characterisation of human dipeptidyl peptidase IV expressed in Pichia pastoris.: A structural and mechanistic comparison between the recombinant human and the purified porcine enzyme [J].
Bär, J ;
Weber, A ;
Hoffmann, T ;
Stork, J ;
Wermann, M ;
Wagner, L ;
Aust, S ;
Gerhartz, B ;
Demuth, HU .
BIOLOGICAL CHEMISTRY, 2003, 384 (12) :1553-1563
[4]   Modulation of hematopoietic stem cell homing and engraftment by CD26 [J].
Christopherson, KW ;
Hangoc, G ;
Mantel, CR ;
Broxmeyer, HE .
SCIENCE, 2004, 305 (5686) :1000-1003
[5]   Type 2 diabetes - Therapy with dipeptidyl peptidase IV inhibitors [J].
Demuth, HU ;
McIntosh, CHS ;
Pederson, RA .
BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS, 2005, 1751 (01) :33-44
[6]   Effect of neuropeptide Y on inflammatory paw edema in the rat:: involvement of peripheral NPYY1 and Y5 receptors and interaction with dipeptidyl-peptidase IV (CD26) [J].
Dimitrijevic, M ;
Stanojevic, S ;
Vujic, V ;
Kovacevic-Jovanovic, V ;
Beck-Sickinger, A ;
Demuth, HU ;
von Hörsten, S .
JOURNAL OF NEUROIMMUNOLOGY, 2002, 129 (1-2) :35-42
[7]   The biology of incretin hormones [J].
Drucker, DJ .
CELL METABOLISM, 2006, 3 (03) :153-165
[8]   IL-3 induces down-regulation of CCR3 protein and mRNA in human eosinophils [J].
Dulkys, Y ;
Kluthe, C ;
Buschermöhle, T ;
Barg, I ;
Knöss, S ;
Kapp, A ;
Proudfoot, AEI ;
Elsner, J .
JOURNAL OF IMMUNOLOGY, 2001, 167 (06) :3443-3453
[9]   Differential activation of CC chemokine receptors by AOP-RANTES [J].
Elsner, J ;
Mack, M ;
Brühl, H ;
Dulkys, Y ;
Kimmig, D ;
Simmons, G ;
Clapham, PR ;
Schlöndorff, D ;
Kapp, A ;
Wells, TNC ;
Proudfoot, AEI .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (11) :7787-7794
[10]   Chemokine receptor antagonists: a novel therapeutic approach in allergic diseases [J].
Elsner, J ;
Escher, SE ;
Forssmann, U .
ALLERGY, 2004, 59 (12) :1243-1258