Signal transduction pathway of interleukin-4 and interleukin-13 in human B cells derived from X-linked severe combined immunodeficiency patients.

Interleukin-4 (IL-4) and IL-13 are functionally similar cytokines. The functional IL-4 receptor (IL-4R) consists of the IL-4R alpha chain (IL-4R alpha) and the IL-2R gamma chain (gamma c), which is shared by the IL-2, IL-7, IL-9, and IL-15 receptors. The functional IL-13R is thought to involve the IL-4R alpha but not gamma c. In this study, we have analyzed activation of members of the Janus tyrosine kinase (Jak) family and signal transducers and activators of transcription (STAT) 6 induced by IL-4 and IL-13 in Epstein-Barr virus-transformed B cells derived from two patients of X-linked severe combined immunodeficiency, who have mutations of the gamma c gene in the extracellular and intracellular domains. In these B cells, IL-4 failed to induce tyrosine phosphorylation of Jak3 and activation of STAT6, or activation of these molecules was significantly decreased compared with Epstein-Barr virus-transformed normal B cells. In contrast, IL-13 activated STAT6 in these cells as well as normal B cells. However, Jak3 was not activated by IL-13, even in normal B cells. These results clearly indicated that gamma c is essential for activation of Jak3 and STAT6 in the signal transduction pathway of IL-4 in human B cells and that IL-13 does not utilize gamma c but activates STAT6 through an alternative pathway, which is not impaired in B cells of X-linked severe combined immunodeficiency patients.