Mechanism of thymus- and activation-regulated chemokine (TARC)/CCL17 production and its modulation by roxithromycin

Abstract

Stimulation with tumor necrosis factor (TNF)α and interferon (IFN)γ synergistically induced thymus- and activation-regulated chemokine (TARC)/CCL17 production from HaCaT keratinocytes (KC). Inhibitors for nuclear factor kappa B (NFκB), parthenolide, and Bay 11-7085, and an inhibitor of p38, SB202190, inhibited TNFα- and IFNγ-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 IFNγ and TNFα. RXM partially suppressed p38 phosphorylation and NFκB-driven luciferase activity induced by TNFα and IFNγ. Degradation of inhibitor of nuclear factor kappa B (IκB) α upon stimulation with IFNγ and TNFα 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 NFκB, independent of the inhibition of IκB degradation. Copyright © 2005 by The Society for Investigative Dermatology, Inc.