title: Differential regulation of eotaxin-1/CCL11 and eotaxin-3/CCL26 production by the TNF-alpha and IL-4 stimulated human lung fibroblast.
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.
authors.affiliation: Division of Clinical Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Rokudai
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Terui
authors.forename: Ryoko
authors.initials: R
authors.lastname: Kuniyoshi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishima
authors.forename: Yuko
authors.initials: Y
authors.lastname: Mishima
authors.forename: Eriko
authors.initials: E
authors.lastname: Aizu-Yokota
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Sonoda
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kasahara
authors.forename: Kiyohiko
authors.initials: K
authors.lastname: Hatake
mesh_terms: D001249:Asthma / Q000276:immunology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002460:Cell Line; D054413:Chemokine CCL11 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000276:immunology; D000075906:Chemokine CCL26; D019742:Chemokines, CC / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000276:immunology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology; D015151:Immunoblotting; D015847:Interleukin-4 / Q000276:immunology / Q000494:pharmacology* / Q000502:physiology; D007976:Leupeptins / Q000494:pharmacology; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D016328:NF-kappa B / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000276:immunology / Q000494:pharmacology; D050800:STAT6 Transcription Factor / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology* / Q000502:physiology
chemical_list: D001897:Boronic Acids; C515456:CCL11 protein, human; C120429:CCL26 protein, human; D054413:Chemokine CCL11; D000075906:Chemokine CCL26; D019742:Chemokines, CC; D004791:Enzyme Inhibitors; D007976:Leupeptins; D016328:NF-kappa B; D011719:Pyrazines; D011994:Recombinant Proteins; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D014409:Tumor Necrosis Factor-alpha; C063261:acetylleucyl-leucyl-norleucinal; D015847:Interleukin-4; D000069286:Bortezomib; D020928:Mitogen-Activated Protein Kinases