INTERLEUKIN-13 IS A POTENT ACTIVATOR OF JAK3 AND STAT6 IN CELLS EXPRESSING INTERLEUKIN-2 RECEPTOR-GAMMA AND INTERLEUKIN-4 RECEPTOR-ALPHA

The lymphocyte growth factors interleukin-2 (IL2), IL4, IL7, IL9 and I L15 use the common IL2 receptor-gamma (IL2R gamma) and activate the IL 2R gamma-associated tyrosine kinase JAK3 (Janus kinase 3). IL13 is str ucturally related to IL4, competes with IL4 for binding to cell surfac e receptors and exhibits many similar biological effects. The molecula r basis for this functional overlap between IL4 and IL13 has been attr ibuted mainly to a shared use of the 140 kDa IL4R alpha, since these c ytokines appear to be uniquely different in that, according to several recent reports, IL13 does not recruit the IL2R gamma or JAK3. This no tion has been supported by the identification of a novel 70 kDa IL13 r eceptor in certain IL13-responsive cell lines that lack IL2R gamma. Th e present study sheds new light on the issue of functional overlap bet ween IL13 and IL4, by demonstrating for the first time that, in cells that express both IL2R gamma and IL4R alpha, IL13 can mimic IL4-induce d heterodimerization of IL2R gamma and IL4R alpha, with consequent mar ked activation of JAK3 and the transcription factor STAT6 (IL4-STAT). Reconstitution experiments in BA/F3 cells showed that both cytokines r equire the simultaneous presence of IL4R alpha and IL2R gamma to media te JAK3 and proliferative responses, and analysis of 12 IL4R alpha var iants showed that IL4 and IL13 signals were equally affected by mutati ons of the cytoplasmic domain. We conclude that IL13 activates the IL2 R gamma-associated JAK3 tyrosine kinase in appropriate cell types, and propose that IL13 is capable of interacting with multiple receptor su bunits in a cell-dependent and combinatorial manner. Consequently, we predict that partial disruption of IL13 signal transduction also contr ibutes to the severe combined immunodeficiency syndromes associated wi th inactivation of the IL2R gamma or JAK3 genes.