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标题：Differential Regulation of Eotaxin-1/CCL11 and Eotaxin-3/CCL26 Production by the TNF-α and IL-4 Stimulated Human Lung Fibroblast
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作者：Akiko Rokudai ; Yasuhito Terui ; Ryoko Kuniyoshi 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：2006
卷号：29
期号：6
页码：1102-1109
DOI：10.1248/bpb.29.1102
出版社：The Pharmaceutical Society of Japan
摘要：Allergic asthma and allergic dermatitis are chronic inflammatory diseases and are characterized by an accumulation of eosinophils at sites of inflammation. Eotaxin-1/CCL11 and eotaxin-3/CCL26 are members of the CC chemokine family, which are known to be potent chemoattractants for eosinophils. We observed that a human lung fibroblast, HFL-1 produces eotaxin-1 and -3 in response to TNF-α plus IL-4 stimulation, accompanied with NF-κB and STAT6 activation. We explored which signaling pathways are operative in the production of eotaxin-1 and -3 using several inhibitors. Eotaxin-1/CCL11 production was inhibited by a p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, but not by the MEK (MAPK/ERK kinase) inhibitors, PD98059 and U0126. In contrast, eotaxin-3/CCL26 production was inhibited similarly by PD98059 as well as U0126 and SB203580. In addition, two proteasome inhibitors, N -acetyl-leucyl-leucyl-norleucinal (ALLN) and bortezomib with significant inhibitory activity on NF-κB activation, inhibited eotaxin-1/CCL11 production with IC₅₀ 8 μ M for ALLN and IC₅₀ 16 n M for bortezomib. In contrast, eotaxin-3/CCL26 production was not inhibited significantly up to 10 μ M of ALLN (IC₅₀16 μ M ) and up to 10 n M of bortezomib (IC₅₀ 11 n M ), giving inhibition of eotaxin-3/CCL26 less sensitive than eotaxin-1/CCL11 production by the proteasome inhibitors. Synergistic inhibition was observed among lower doses of SB203580 and proteasome inhibitors, particularly in the eotaxin-1/CCL11 production. No such prominent synergism was found on the eotaxin-3/CCL26 production. The suppression of eotaxin family production by these inhibitors may be efficacious against allergic diseases.
关键词：eotaxin-1;eotaxin-3;lung fibroblast;NF-κB activation;proteasome inhibitor