title: 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.
authors.affiliation: Clinic for Immunology and Rheumatology, Hannover Medical School, Hannover, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Forssmann
authors.forename: Carsten
authors.initials: C
authors.lastname: Stoetzer
authors.forename: Michael
authors.initials: M
authors.lastname: Stephan
authors.forename: Carsten
authors.initials: C
authors.lastname: Kruschinski
authors.forename: Thomas
authors.initials: T
authors.lastname: Skripuletz
authors.forename: Jutta
authors.initials: J
authors.lastname: Schade
authors.forename: Andreas
authors.initials: A
authors.lastname: Schmiedl
authors.forename: Reinhard
authors.initials: R
authors.lastname: Pabst
authors.forename: Leona
authors.initials: L
authors.lastname: Wagner
authors.forename: Torsten
authors.initials: T
authors.lastname: Hoffmann
authors.forename: Astrid
authors.initials: A
authors.lastname: Kehlen
authors.forename: Sylvia E
authors.initials: SE
authors.lastname: Escher
authors.forename: Wolf-Georg
authors.initials: WG
authors.lastname: Forssmann
authors.forename: Jörn
authors.initials: J
authors.lastname: Elsner
authors.forename: Stephan
authors.initials: S
authors.lastname: von Hörsten
mesh_terms: D000818:Animals; D054413:Chemokine CCL11 / Q000276:immunology* / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D018819:Dipeptidyl Peptidase 4 / Q000276:immunology / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004804:Eosinophils / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007532:Isoleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D011922:Rats, Mutant Strains; D054397:Receptors, CCR3 / Q000378:metabolism; D012867:Skin / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology
chemical_list: C515350:CCR3 protein, human; D054413:Chemokine CCL11; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004791:Enzyme Inhibitors; D054397:Receptors, CCR3; D013844:Thiazoles; C114061:isoleucyl-thiazolidide; D007532:Isoleucine; D018819:Dipeptidyl Peptidase 4