n-Nonanoyl-CC chemokine ligand 14, a potent CC chemokine ligand 14 analogue that prevents the recruitment of eosinophils in allergic airway inflammation.
CCR3 is responsible for tissue infiltration of eosinophils, basophils, mast cells, and Th2 cells, particularly in allergic diseases. In this context, CCR3 has emerged as a target for the treatment of allergic asthma. It is well known that the N-terminal domain of chemokines is crucial for receptor binding and, in particular, its activation. Based on this background, we investigated a number of N-terminally truncated or modified peptides derived from the chemokine CCL14/hemofiltrate CC chemokine-1 for their ability to modulate the activity of CCR3. Among 10 derivatives tested, n-nonanoyl (NNY)-CCL14[10-74] (NNY-CCL14) was the most potent at evoking the release of reactive oxygen species and inducing chemotaxis of human eosinophils. In contrast, NNY-CCL14 has inactivating properties on human eosinophils, because it is able to induce internalization of CCR3 and to desensitize CCR3-mediated intracellular calcium release and chemotaxis. In contrast to naturally occurring CCL11, NNY-CCL14 is resistant to degradation by CD26/dipeptidyl peptidase IV. Because inhibition of chemokine receptors through internalization is a reasonable therapeutic strategy being pursued for HIV infection, we tested a potential inhibitory effect of NNY-CCL14 in two murine models of allergic airway inflammation. In both OVA- and Aspergillus fumigatus-sensitized mice, i.v. treatment with NNY-CCL14 resulted in a significant reduction of eosinophils in the airways. Moreover, airway hyper-responsiveness was shown to be reduced by NNY-CCL14 in the OVA model. It therefore appears that an i.v. administered agonist internalizing and thereby inhibiting CCR3, such as NNY-CCL14, has the potential to alleviate CCR3-mediated diseases.
IPF PharmaCeuticals, An-Institut of Hannover Medical School, Germany. u.forssmann@ipf-pharma.de
Ulf
U
Forssmann
Inka
I
Hartung
Ralf
R
Bälder
Barbara
B
Fuchs
Sylvia E
SE
Escher
Nikolaj
N
Spodsberg
Yasmin
Y
Dulkys
Michael
M
Walden
Aleksandra
A
Heitland
Armin
A
Braun
Wolf-Georg
WG
Forssmann
Jörn
J
Elsner
D000818:Animals; D002465:Cell Movement / Q000276:immunology / Q000502:physiology*; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000378:metabolism*; D002633:Chemotaxis / Q000276:immunology / Q000502:physiology; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000819:agonists; D012137:Respiratory System / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors
C515456:CCL11 protein, human; C097720:CCL14 protein, human; C515350:CCR3 protein, human; C515457:Ccl11 protein, mouse; C515351:Ccr3 protein, mouse; D054413:Chemokine CCL11; D019742:Chemokines, CC; D054397:Receptors, CCR3; D019707:Receptors, Chemokine