Manns J, Rieder S, Escher S, Eilers B, Forssmann W-G, Elsner J, Forssmann U
IPF Pharmaceuticals GmbH, An-Institut of Hannover Medical School, Hannover, Germany.
Allergy. 2007 Jan;62(1):17-24. doi: 10.1111/j.1398-9995.2006.01230.x.
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.
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.
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.
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.
CC趋化因子配体11（CCL11）是所有已描述的CC趋化因子受体3（CCR3）配体中的杰出成员，并且已证明对该受体具有选择性。然而，它也能激活CCR5，但仅在微摩尔范围内。CCL11的体内活性预计会受到时间限制，因为它会被特定的蛋白酶如二肽基肽酶IV（DP4，也称为CD26）降解。基于在过敏性疾病模型中使趋化因子受体失活的方法，如已证明的对DP4抗性的正壬酰基（NNY）-CCL14和氨基氧基戊烷（AOP）-CCL5，研究源自CCL11的类似化合物很有吸引力。
进行了NNY-CCL11的合成，并对其在人和小鼠嗜酸性粒细胞以及稳定转染人CCR3或CCR5的细胞系中的生物学功能进行了表征。还研究了其对DP4处理的抗性。
通过CCR3介导的NNY-CCL11的功能活性在细胞内钙动员和CCR3内化方面显示出与CCL11几乎相同的模式。用DP4预孵育导致CCL11的N端裂解，从而降低CCR3内化能力，而NNY-CCL11的预孵育则无影响。与CCL11相反，NNY-CCL11还能在纳摩尔范围内激活CCR5 +细胞系和人单核细胞，其效力比CCL11高约100倍。
正壬酰基-CCL11是一种具有仅限于CCR3和CCR5的双重活性的化合物。由于其受体失活能力和对DP4降解的稳定性，NNY-CCL11是用于解读过敏性疾病病理生理机制的合适工具。
