Two different IL-13 receptor chains are expressed in normal human skin fibroblasts, and IL-4 and IL-13 mediate signal transduction through a common pathway

IL-13 and IL-4, pleiotropic immune regulatory cytokines, have been shown to mediate similar prominent effects in human fibroblast cell lines, However, molecular mechanisms for their redundant effects are not known. Here, we have investigated the structure of IL-13 receptors (IL-13R) and molecular mechanisms of signal transduction through IL-13 and IL-4 receptors in non-transformed normal skin fibroblast cell lines. We demonstrate that high-affinity IL-13R is expressed in normal skin fibroblast cell lines. Upon [I-125]IL-13 cross-linking, a similar to 60-70 kDa band was observed in sk559 and sk574 fibroblast cell lines. By RT-PCR analysis, mRNA for IL-13R alpha, IL-13R alpha' and IL-4R beta chains were expressed; however, the lL-2R gamma chain, shown to participate and modulate IL-4 and IL-13 binding, was not expressed in any of the cell lines examined, The Janus kinase (JAK)2 and Tyk2 were phosphorylated in response to IL-4 or IL-13 in sk559 and sk574 cell lines, JAK1 was also phosphorylated in one of two cell lines while JAK3 was present but not phosphorylated in any of the cell lines studied, A signal transduction and activator of transcription (STAT)6 was also activated in response to both IL. An insulin receptor substrate (IRS)-1 was constitutively phosphorylated and its phosphorylation level was augmented in response to both IL, These results suggest that the mechanism of signal transduction through IL-13 and IL-4 receptors in human fibroblast cell lines is similar, and this may, at least in part, be responsible for the redundant effects of these two cytokines, In addition, JAK2 tyrosine kinase instead of JAK3 appears to play a major role in IL-4- and IL-13-induced signal transduction in human fibroblasts.