Unusual interleukin-4 and-13 signaling in human normal and tumor lung fibroblasts

IL-4 and IL-13 act on human lung fibroblasts through specific receptors dif fering in their composition. Indeed, the gammac chain is constitutively exp ressed in tumor lung myofibroblast but not in normal cells, Here, we have a nalysed the signal transduction induced by IL-4 and IL-13 in both cell type s, in order to better understand the molecular mechanisms underlying tumor stromal development. The IL-4R alpha chain is constitutively phosphorylated and pre-associated with the JAK1 protein in both cell types. In normal cel ls, we detected the activation of the classic IRS-2 or JAK1/STAT6 pathways, the phosphorylation of JAK2, while Tyk2 was constitutively phosphorylated and not modified by both cytokines, In addition to these pathways, in lung tumor myofibroblasts, IL-4 and IL-13 induced the phosphorylation of JAK3 an d increased the phosphorylation of Tyk2, Interestingly, in both cell types IL-4 and IL-13 triggered an unusual pattern of STAT1 and STAT3 activation. These events probably correspond to a tissue-specific signaling important f or the immunoregulatory functions of airways fibroblasts, Indeed, the infla mmatory-like pattern of STATs signaling triggered by IL-4 and IL-13 in thes e cells may favor the homing of inflammatory and/or metastatic cells. In lu ng myofibroblasts, these properties could be modified through the different pattern of JAK activation.