Differential Regulation of Eotaxin-1/CCL11 and Eotaxin-3/CCL26 Production by the TNF-α and IL-4 Stimulated Human Lung Fibroblast(Pharmacology)

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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 IC_<50> 8μM for ALLN and IC_<50> 16nM for bortezomib. In contrast, eotaxin-3/CCL26 production was not inhibited significantly up to 10μM of ALLN (IC_<50> 16μM) and up to 10nM of bortezomib (IC_<50> 11nM), 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.
社団法人日本薬学会の論文
2006-06-01

Differential Regulation of Eotaxin-1/CCL11 and Eotaxin-3/CCL26 Production by the TNF-α and IL-4 Stimulated Human Lung Fibroblast(Pharmacology)

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