RRC ID 42663
Author Rokudai A, Terui Y, Kuniyoshi R, Mishima Y, Mishima Y, Aizu-Yokota E, Sonoda Y, Kasahara T, Hatake K.
Title Differential regulation of eotaxin-1/CCL11 and eotaxin-3/CCL26 production by the TNF-alpha and IL-4 stimulated human lung fibroblast.
Journal Biol Pharm Bull
Abstract 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-alpha plus IL-4 stimulation, accompanied with NF-kappaB 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-kappaB activation, inhibited eotaxin-1/CCL11 production with IC50 8 microM for ALLN and IC50 16 nM for bortezomib. In contrast, eotaxin-3/CCL26 production was not inhibited significantly up to 10 microM of ALLN (IC50 16 microM) and up to 10 nM of bortezomib (IC50 11 nM), 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.
Volume 29(6)
Pages 1102-9
Published 2006-6-1
DOI 10.1248/bpb.29.1102
PII JST.JSTAGE/bpb/29.1102
PMID 16755001
MeSH Asthma / immunology Boronic Acids / pharmacology Bortezomib Cell Line Chemokine CCL11 / antagonists & inhibitors Chemokine CCL11 / biosynthesis* Chemokine CCL11 / immunology Chemokine CCL26 Chemokines, CC / antagonists & inhibitors Chemokines, CC / biosynthesis* Chemokines, CC / immunology Drug Synergism Enzyme Inhibitors / pharmacology Fibroblasts / drug effects* Fibroblasts / immunology Humans Hypersensitivity / immunology Immunoblotting Interleukin-4 / immunology Interleukin-4 / pharmacology* Interleukin-4 / physiology Leupeptins / pharmacology Lung / cytology Lung / drug effects* Lung / immunology Mitogen-Activated Protein Kinases / antagonists & inhibitors NF-kappa B / metabolism Pyrazines / pharmacology Recombinant Proteins / immunology Recombinant Proteins / pharmacology STAT6 Transcription Factor / metabolism Tumor Necrosis Factor-alpha / immunology Tumor Necrosis Factor-alpha / pharmacology* Tumor Necrosis Factor-alpha / physiology
IF 1.54
Times Cited 28
Human and Animal Cells