The effect of pharmacological PI3K纬 inhibitor on eotaxin-induced human eosinophil functions

详细信息    查看全文

• 作者：Yukiko Saito¹ ; Masahide Takeda ; ¹ ; ^{takeda-56@hos.akita-u.ac.jp" class="auth_mail} ; Junko Nishikawa ; Yasunori Konno ; Mami Tamaki ; Masamichi Itoga ; Yoshiki Kobayashi ; Yuki Moritoki ; Wataru Ito ; Junichi Chihara ; Shigeharu Ueki
• 关键词：Asthma ; Eosinophil ; Eotaxin ; PI3K纬
• 刊名：Pulmonary Pharmacology & Therapeutics
• 出版年：April, 2014
• 年：2014
• 卷：27
• 期：2
• 页码：164-169
• 全文大小：786 K

文摘

Background

Asthma is characterized by chronic inflammation caused by activation of immune cells including Th2 lymphocytes and eosinophils. Phosphoinositide 3-kinase (PI3K) 纬 deficient asthmatic mice聽did not develop lung eosinophilia, although the detailed mechanisms are not well known. A CC chemokine eotaxin (CCL11) plays a prominent role in developing eosinophilic inflammation through CCR3. In this study, we tested the roles of PI3K纬 in eotaxin-induced eosinophil functions using a pharmacological inhibitor.

Method

Human peripheral blood eosinophils were isolated by CD16-negative selection method. The effect of AS605240, synthetic PI3K纬 inhibitor on eotaxin-induced adhesion, chemotaxis, and degranulation were studied using intracellular adhesion molecule-1 (ICAM-1)-coated plates, Boyden chamber system, ELISA for eosinophil-derived neurotoxin (EDN) levels in the culture supernatant, respectively. CCR3 expression levels and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation were assessed by flowcytometry. Involvement of PI3K纬 in spontaneous apoptosis was studied using flowcytometry.

Results

Although AS605240 did not affect the eosinophil spontaneous apoptosis, eotaxin-induced chemotaxis, adhesion to ICAM-1 coated plate, and EDN release were inhibited by AS605240. AS605240 also inhibited the eotaxin-induced ERK1/2 phosphorylation without down-regulation of surface CCR3 expression.

Conclusion

These results indicate that PI3K纬 inhibitor attenuates eotaxin-induced eosinophil functions by suppressing the downstream signaling of CCR3 without significant cytotoxicity. PI3K纬 plays an important role in the development of eosinophilic inflammation and blockade of PI3K纬 might be a therapeutic strategy for treatment of eosinophil-related diseases including asthma.