The allergy-associated chemokine receptors CCR3 and CCR5 can be inactivated by the modified chemokine NNY-CCL11.
BACKGROUND
CC chemokine ligand 11 (CCL11) is the outstanding member of all described CC chemokine receptor 3 (CCR3) ligands and is shown to be selective for this receptor. However, it also activates CCR5 but only in the micromolar range. The in vivo activity of CCL11 is expected to be temporally restricted, as it is degraded by specific proteases such as the dipeptidyl-peptidase IV (DP4), also termed CD26. Based on the approach to inactivate chemokine receptors in allergic disease models as has been demonstrated for DP4-resistant n-nonanoyl (NNY)-CCL14 and for amino-oxypentane (AOP)-CCL5, it is tempting to study similar compounds derived from CCL11.


METHODS
Synthesis of NNY-CCL11 was performed and it was characterized for biological functions in human and mouse eosinophils as well as in cell lines stably transfected either with human CCR3 or CCR5. Resistance to DP4 treatment was also investigated.


RESULTS
The functional activities of NNY-CCL11 mediated via CCR3 show an almost identical pattern to CCL11 with respect to intracellular calcium mobilization and CCR3 internalization. N-terminal cleavage of CCL11 by preincubation with DP4 results in a reduced capacity to internalize CCR3, while preincubation of NNY-CCL11 shows no influence. In contrast to CCL11, NNY-CCL11 also activates CCR5+ cell lines and human monocytes in the nanomolar range, being about 100 times more potent than CCL11.


CONCLUSIONS
n-Nonanoyl-CCL11 represents a compound with dual activity restricted to CCR3 and CCR5. Because of its receptor-inactivating capacity and stability against DP4 degradation, NNY-CCL11 is a suitable tool for the decoding of the pathophysiological mechanisms of allergic diseases.
Manns
J
J
IPF Pharmaceuticals GmbH, An-Institut of Hannover Medical School, Hannover, Germany.
Rieder
S
S
Escher
S
S
Eilers
B
B
Forssmann
W-G
WG
Elsner
J
J
Forssmann
U
U
D000243:Adenosine Deaminase / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000737:chemistry* / Q000378:metabolism*; D018819:Dipeptidyl Peptidase 4 / Q000502:physiology; D004804:Eosinophils / Q000378:metabolism; D005260:Female; D006023:Glycoproteins / Q000502:physiology; D006801:Humans; D006967:Hypersensitivity / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000378:metabolism; D054397:Receptors, CCR3; D019713:Receptors, CCR5 / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D022161:Transport Vesicles / Q000378:metabolism
C519278:CC chemokine ligand 11, N-nonanoyl(1)-; C515456:CCL11 protein, human; C515350:CCR3 protein, human; C515457:Ccl11 protein, mouse; C515351:Ccr3 protein, mouse; D054413:Chemokine CCL11; D019742:Chemokines, CC; D006023:Glycoproteins; D054397:Receptors, CCR3; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D011994:Recombinant Proteins; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000243:Adenosine Deaminase; D002118:Calcium