Induction of the IL-13 receptor alpha 2-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-inflam matory effects depending on the cell type they act upon and the nature of t he receptors expressed. The type I receptor complex is composed of the IL-4 R alpha and gammac and only binds IL-4, whereas, in the type II receptor, I L-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 recept or has been described, the IL-13R alpha2, but the regulation of its express ion and its role in IL-4/IL-13 transduction is poorly understood. In this s tudy we report that IL-4 and IL-13 upregulate IL-13R alpha2 at both the mRN A and protein levels in the keratinocyte cell line HaCaT. In these cells, I L-4 or IL-13 were shown to activate the Janus Kinases JAK1 and JAK2, the tr anscription factor STAT6, and the ERK and p38 mitogen-activated protein kin ases. 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 les ser extent, the p38 MAPK inhibitor SB203580. Moreover, expression of a cons titutive active mutant of STAT6 alone did not modify IL-13R alpha2 mRNA exp ression, but potentiated the effects of IL-4 or 11-13 on IL-13 alpha2 expre ssion. The constitutive active mutants of MEK1 or MKK6 increased the level of expression of IL-13R alpha2 mRNA even in absence of stimulation. Our fin dings demonstrate, for the first time, that IL-4 and IL-13 can induce IL-13 R alpha2 expression in keratinocytes, and that the ERK and p38 MAPK togethe r with JAK2 and STAT6 play a critical role in this process.