Induction of the IL-13 receptor α2-chain by IL-4 and IL-13 in human keratinocytes: involvement of STAT6, ERK and p38 MAPK pathways

Abstract

IL-4 and IL-13 are related cytokines which induce both pro-and anti-in¯ammatory e ects depending on the cell type they act upon and the nature of the receptors expressed. The type I receptor complex is composed of the IL-4Ra and gc and only binds IL-4, whereas, in the type II receptor, IL-4Ra dimerizes with IL-13Ra1 upon either IL-4 or IL-13 binding. Another ligand binding chain potentially implicated in the IL-4/IL-13 receptor has been described, the IL-13Ra2, but the regulation of its expression and its role in IL-4/IL-13 transduction is poorly understood. In this study we report that IL-4 and IL-13 upregulate IL-13Ra2 at both the mRNA and protein levels in the keratinocyte cell line HaCaT. In these cells, IL-4 or IL-13 were shown to activate the Janus Kinases JAK1 and JAK2, the transcription factor STAT6, and the ERK and p38 mitogen-activated protein kinases. We show that IL-4 or IL-13-induced IL-13Ra2 mRNA expression was inhibited by the ERK inhibitor U0126, the JAK inhibitor AG490 and, to a lesser extent, the p38 MAPK inhibitor SB203580. Moreover, expression of a constitutive active mutant of STAT6 alone did not modify IL-13Ra2 mRNA expression, but potentiated the e ects of IL-4 or IL-13 on IL-13Ra2 expression. The constitutive active mutants of MEK1 or MKK6 increased the level of expression of IL-13Ra2 mRNA even in absence of stimulation. Our ®ndings demonstrate, for the ®rst time, that IL-4 and IL-13 can induce IL-13Ra2 expression in keratinocytes, and that the ERK and p38 MAPK together with JAK2 and STAT6 play a critical role in this process. Oncogene (2001) 20, 6660 ± 6668.

Lysophosphatidic Acid Induces Interleukin-13 (IL-13) Receptor α2 Expression and Inhibits IL-13 Signaling in Primary Human Bronchial Epithelial Cells

“…1). These results are similar to studies by two other research groups, David et al (60) and Yasunaga et al (29), who found that the Th2 cytokines IL-4 and IL-13 induce IL-13R␣2 gene expression without affecting IL-13R␣1 and IL-4R␣. Ours is the first report showing that a lysophospholipid can regulate IL-13R␣2 expression.…”

Level of Expression of IL-13Rα2 Impacts Receptor Distribution and IL-13 Signaling

“…The inability of IL-13R␣2 expression to confer IL-13 responsiveness despite high affinity binding, along with the finding of soluble IL-13R␣2 in vivo (9), has led to speculation that IL-13R␣2 is a decoy receptor. Expression of IL-13R␣2 varies across cell types and can be induced by inflammation and cytokines (15)(16)(17)(18)(19)(20). A role for IL-13R␣2 as a potential modulator of inflammation in asthma is suggested by the IL-13-and IL-4-dependent up-regulation of IL-13R␣2 in primary bronchial epithelial cells and the demonstration that overexpression of IL-13R␣2 in bronchial derived cells decreases IL-13-dependent Stat6 phosphorylation (21).…”

IL-4 and IL-13 Negatively Regulate TNF-α- and IFN-γ-Induced β-Defensin Expression through STAT-6, Suppressor of Cytokine Signaling (SOCS)-1, and SOCS-3

“…STAT-6 is activated by the binding of IL-4 and/or IL-13 to the heterodimerized IL-4R␣:IL-13R␣1 (30). It then translocates to the nucleus where it inhibits the binding of NF-B to promoter sequences and subsequent gene expression (31).…”