CCL26-targeted siRNA treatment of alveolar type II cells decreases expression of CCR3-binding chemokines and reduces eosinophil migration: implications in asthma therapy.
The underlying inflammation present in chronic airway diseases is orchestrated by increased expression of CC chemokines that selectively recruit leukocyte populations into the pulmonary system. Human CCL26 signals through CC chemokine receptor 3 (CCR3), is dramatically upregulated in challenged asthmatics, and stimulates recruitment of eosinophils (EOSs) and other leukocytes. CCL26 participates in regulation of its receptor CCR3 and modulates expression of a variety of chemokines in alveolar type II cells. Utilizing the A549 alveolar type II epithelial cell culture model, we carried out studies to test the hypothesis that CCL26-siRNA treatment of these cells would ameliorate Th2-driven release of the eotaxins and other CCR3 ligands that would, in turn, decrease recruitment and activation of EOSs. Results demonstrate that CCL26-siRNA treatments decreased interleukin-4-induced CCL26 and CCL24 expression by >70%. CCL26-directed small-interfering RNA (siRNA) treatments significantly decreased release of CCL5 (RANTES), CCL15 (MIP-1δ), CCL8 (MCP-2), and CCL13 (MCP-4). In bioactivity assays it was shown that EOS migration and activation were reduced up to 80% and 90%, respectively, when exposed to supernatants of CCL26-siRNA-treated cells. These results provide evidence that CCL26 may be an appropriate target for development of new therapeutic agents designed to alleviate the underlying inflammation associated with chronic diseases of the airways.
Errahali
Younes J
YJ
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida 32307, USA.
Taka
Equar
E
Abonyo
Barack O
BO
Heiman
Ann S
AS
D001249:Asthma / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D000075906:Chemokine CCL26; D019742:Chemokines, CC / Q000235:genetics*; D004804:Eosinophils / Q000166:cytology* / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D011650:Pulmonary Alveoli / Q000166:cytology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics*; D054397:Receptors, CCR3 / Q000276:immunology / Q000378:metabolism*
C120429:CCL26 protein, human; D000075906:Chemokine CCL26; D019742:Chemokines, CC; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D054397:Receptors, CCR3