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 CR) consists of the IL-4R alpha chain (I L-4R alpha) and the IL-2R gamma chain (gamma(c)), which is shared by t he IL-2, IL-7, IL-9, and IL-15 recep tors. The functional IL-13R is th ought to involve the IL-4R alpha but not gamma(c). In this study, we h ave 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 d erived from two patients of X-linked severe combined immunodeficiency, who have mutations of the gamma(c) gene in the extracellular and intr acellular domains. In these B cells, IL-4 failed to induce tyrosine ph osphorylation 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 the se 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 g amma(c) is essential for activation of Jak3 and STAT6 in the signal tr ansduction pathway of IL-4 in human B cells and that IL-13 does not ut ilize gamma(c) but activates STAT6 through an alternative pathway, whi ch is not impaired in B cells of X-linked severe combined immunodefici ency patients.