| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
,¶
* Clinic for Immunology and Rheumatology and
Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany;
Probiodrug AG, Halle/Saale, Germany;
Department of Dermatology and Allergology, Fachklinik Bad Bentheim, Bad Bentheim, Germany; and
¶ Franz-Penzoldt Center, Experimental Therapy, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the HILF-II program of the Hannover Medical School (to S.v.H. and J.E.) as well as by grants from the Deutsche Forschungsgemeinschaft (1. SFB 587; Project B11 to S.v.H., A.S., and J.S.; 2. FO77/10-1 to W.G.F. and J.E.).
2 Current address: Merck KGaA Darmstadt, Germany.
3 Address correspondence and reprint requests to Dr. Stephan von Hörsten, Experimental Therapy, Franz-Penzoldt-Center, Friedrich-Alexander-University Erlangen-Nürnberg, Palmsanlage 5, 91056 Erlangen, Germany. E-mail address: Stephan.v.Hoersten{at}ze.uni-erlangen.de
4 Abbreviations used in this paper: DPPIV, dipeptidyl peptidase IV; MS, mass spectrometry; ABC, avidin-biotin complex; APAAP, alkaline phosphatase-anti-alkaline phosphatase; TFA, trifluoroacetic acid.
Related articles in The JI:
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
