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Small molecule antagonists of CCR8 inhibit eosinophil and T cell migration.

Abstract：

:In this study, we demonstrate that in addition to T lymphocytes, human naïve eosinophils and the differentiated eosinophil-like cell line, AML14.3D10 express CCR8 and respond to CCL1 through CCR8 engagement. The responsiveness of cells was dependent on maturation stage, since CCL1 induced pronounced chemotaxis only in differentiated CCR8 positive AML14.3D10 cells. Despite the low CCR8 surface expression, human naïve eosinophils respond with a chemotaxis to high concentration CCL1. We further describe that Th2 clones in a maturation dependent fashion produce autocrine CCL1, which renders them unresponsive to further stimulation. An innovative method to enrich primary CCR8 reactive T cells was developed which demonstrates that primary peripheral CCR8 expressing T cells respond significantly to CCL1. We have developed novel small molecule CCR8 antagonists that are effective in inhibiting calcium mobilization and chemotaxis in differentiated AML cells as well as in human primary CCR8 positive T cells. Importantly, we demonstrate that the compounds can be divided into two subgroups: (i) compounds that are functional agonists for calcium mobilization and chemotaxis (ii) compounds that are pure antagonists. We demonstrate that agonism of these compounds does not correlate with their antagonistic potency. Taken together, we have identified a novel set of CCR8 compounds with antagonistic properties that inhibit CCL1 driven chemotaxis in both CCR8 expressing eosinophils as well as primary human T cells.

journal_name

Biochem Biophys Res Commun

journal_title

Biochemical and biophysical research communications

authors

Karlsson AK,Walles K,Bladh H,Connolly S,Skrinjar M,Rosendahl A

doi

10.1016/j.bbrc.2011.03.097

subject

Has Abstract

pub_date

2011-04-22 00:00:00

pages

764-71

issue

4

eissn

0006-291X

issn

1090-2104

pii

S0006-291X(11)00494-3

journal_volume

407

pub_type

杂志文章

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