Mechanism of thymus- and activation-regulated chemokine (TARC)/CCL17 production and its modulation by roxithromycin.
Stimulation with tumor necrosis factor (TNF)alpha and interferon (IFN)gamma synergistically induced thymus- and activation-regulated chemokine (TARC)/CCL17 production from HaCaT keratinocytes (KC). Inhibitors for nuclear factor kappa B (NFkappaB), parthenolide, and Bay 11-7085, and an inhibitor of p38, SB202190, inhibited TNFalpha- and IFNgamma-induced production of CCL17 by HaCaT KC. Surprisingly, an inhibitor of epidermal growth factor receptor tyrosine kinase, PD153035, enhanced the production of CCL17 in HaCaT KC. Roxithromycin (RXM), a 14-membered ring macrolide, suppressed CCL17 production by HaCaT KC induced by IFNgamma and TNFalpha. RXM partially suppressed p38 phosphorylation and NFkappaB-driven luciferase activity induced by TNFalpha and IFNgamma. Degradation of inhibitor of nuclear factor kappa B (IkappaB) alpha upon stimulation with IFNgamma and TNFalpha was not affected by the addition of RXM. Through elucidating the mechanism of CCL17 production, our study indicates that RXM suppresses the production through the inhibition of p38 and NFkappaB, independent of the inhibition of IkappaB degradation.
Komine
Mayumi
M
Department of Dermatology, University of Tokyo, Tokyo, Japan. KOMINE-DER@h.u-tokyo.ac.jp
Kakinuma
Takashi
T
Kagami
Shinji
S
Hanakawa
Yasushi
Y
Hashimoto
Koji
K
Tamaki
Kunihiko
K
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D054414:Chemokine CCL17; D019742:Chemokines, CC / Q000378:metabolism*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D015575:Roxithromycin / Q000494:pharmacology*; D012717:Sesquiterpenes / Q000494:pharmacology; D015398:Signal Transduction; D013450:Sulfones / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000900:Anti-Bacterial Agents; C416282:BAY 11-7085; C106230:CCL17 protein, human; D054414:Chemokine CCL17; D019742:Chemokines, CC; D016328:NF-kappa B; D009570:Nitriles; D011799:Quinazolines; D012717:Sesquiterpenes; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha; D015575:Roxithromycin; C002669:parthenolide; D007371:Interferon-gamma; D066246:ErbB Receptors; D048051:p38 Mitogen-Activated Protein Kinases; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline