Inducible Expression of a Th2-Type CC Chemokine Thymus- and Activation-Regulated Chemokine by Human Bronchial Epithelial Cells

Abstract

CCR4 is now known to be selectively expressed in Th2 cells. Since the bronchial epithelium is recognized as an important source of mediators fundamental to the manifestation of respiratory allergic inflammation, we studied the expression of two functional ligands for CCR4, i.e., macrophage-derived chemokine (MDC) and thymus- and activation-regulated chemokine (TARC), in bronchial epithelial cells. The bronchial epithelium of asthmatics and normal subjects expressed TARC protein, and the asthmatics showed more intense expression than the normal subjects. On the other hand, MDC expression was only weakly detected in the asthmatics, but the intensity was not significantly different from that of normal subjects. Combination of TNF-α and IL-4 induced expression of TARC protein and mRNA in bronchial epithelial A549 cells, which was slightly up-regulated by IFN-γ. The enhancement by IFN-γ was more pronounced in bronchial epithelial BEAS-2B cells, and a maximum production occurred with combination of TNF-α, IL-4, and IFN-γ. On the other hand, MDC was essentially not expressed in any of the cultures. Furthermore, expressions of TARC protein and mRNA were almost completely inhibited by glucocorticoids. These results indicate that the airway epithelium represents an important source of TARC, which potentially plays a role via a paracrine mechanism in the development of allergic respiratory diseases. Furthermore, the beneficial effect of inhaled glucocorticoids on asthma may be at least in part due to their direct inhibitory effect on TARC generation by the bronchial epithelium.

IL‐4 induces expression of TARC/CCL17 via two STAT6 binding sites

“…This swift induction appears to be typical, as similar kinetics are seen with many IL-4-induced genes including SOCS-1 [29,38], FIZZ1 [39], Eotaxin/CCL11 [28] and Eotaxin-3/CCL26 [27]. Most other cell types that were examined for IL-4 inducibility of TARC/CCL17 require simultaneous stimulation with TNF-a to up-regulate its expression [8,21,30,33,[40][41][42]. Such cooperative effects of IL-4 and TNF-a stimulation were shown before for other genes.…”

“…Hence, the present work was intended to study the IL-4 inducibility of the expression of TARC/ [27]. Most other cell types that were examined for IL-4 inducibility of TARC/CCL17 require simultaneous stimulation with TNF-a to up-regulate its expression [8,21,30,33,[40][41][42]. Such cooperative effects of IL-4 and TNF-a stimulation were shown before for other genes.…”

“…It encodes a highly basic 94 amino acid residues long preprotein with a cleavage site between Ala23 and Ala24. The mature TARC/CCL17 protein is 71 amino acid residues in length and was shown to be constitutively expressed in thymus [2] and, upon activation with different inducers, in several cell types including PBMC [5], monocytes [6], dendritic cells [7], endothelial cells, and bronchial epithelial cells [8].…”

“…TARC/CCL17 expression is induced by a variety of stimuli including IL-4 [8,[30][31][32]. IL-4-dependent regulation of TARC/CCL17 expression has been shown for airway smooth muscle cells [33], the keratinocyte cell line HaCaT [34] and fibroblasts; the mechanism of this regulation, however, remained uncharacterized.…”

Novel uses for anti‐platelet agents as anti‐inflammatory drugs

“…Indeed, exploiting mediators involved in platelet activation that are disease specific would obviously have advantages. Antagonists for specific chemokine receptors may be advantageous, for example the targeting of platelet CCR3 and CCR4 might be of benefit in treating asthmatics (Gonzalo et al, 1999;Sekiya et al, 2000), while the targeting of RANTES may be beneficial in the treatment of atherosclerosis since platelet-derived RANTES deposited on the surface of endothelial cells is necessary for monocyte accumulation (Von Hundelshausen et al, 2005). Indeed, RANTES receptor antagonists inhibit the infiltration of macrophages, and importantly, reduce neointima formation in ApoE-deficient mice (Schober et al, 2002;Huo et al, 2003).…”