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

IL-4 and IL-13 are related cytokines which induce both pro- and anti-inflammatory effects 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-4R alpha and gammac and only binds IL-4, whereas, in the type II receptor, IL-4R alpha dimerizes with IL-13R alpha1 upon either IL-4 or IL-13 binding. Another ligand binding chain potentially implicated in the IL-4/M-13 receptor has been described, the IL-13R alpha2, 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-13R alpha2 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-13R alpha2 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-13R alpha2 mRNA expression, but potentiated the effects of IL-4 or 11-13 on IL-13 alpha2 expression. The constitutive active mutants of MEK1 or MKK6 increased the level of expression of IL-13R alpha2 mRNA even in absence of stimulation. Our findings demonstrate, for the first time, that IL-4 and IL-13 can induce IL-13R alpha2 expression in keratinocytes, and that the ERK and p38 MAPK together with JAK2 and STAT6 play a critical role in this process.