Interleukin-2 (IL-2)-mediated induction of the IL-2 receptor alpha chain gene

The interleukin-2 receptor alpha chain (IL-2R alpha) is potently induced by antigens, mitogens, and certain cytokines that include IL-2 itself, This induction leads to the formation of high affinity IL-2 receptors when IL-2R alpha is co-expressed with the beta (IL-2R beta) and gamma (gamma(c)) chains of this receptor. We investigated the signaling pathways mediating IL-2-induced IL-2R alpha mRNA expression using 32D myeloid progenitor cells stably transfected with either wild type IL-2R beta or mutants of IL-2R beta containing tyrosine to phenylalanine substitutions, Of the six cytoplasmic tyrosines in IL-2R beta, we have found that only the two tyrosines that mediate Stat5 activation (Tyr-392 and Tyr-510) contribute to IL-2-induced IL-2R alpha gene expression and that either tyrosine alone is sufficient for this process, Interestingly, the IL-7 receptor contains a tyrosine (Tyr-429)-based sequence resembling the motifs encompassing Tyr-392 and Tyr-510 of IL-2R beta. Further paralleling the IL-2 system, IL-7 could activate Stat5 and drive expression of IL-2R alpha mRNA in 32D cells transfected with the human IL-7R. However, IL-3 could not induce IL-2R alpha mRNA in 32D cells, despite its ability to activate Stat5 via the endogenous IL-3 receptor, Moreover, the combination of IL-3 and IL-2 could not ''rescue'' IL-2R alpha mRNA expression in cells containing an IL-2R beta mutant with phenylalanine substitutions at Tyr-392 and Tyr-510, These data suggest that Tyr-392 and Tyr-510 couple to an additional signaling pathway beyond STAT protein activation in IL-2-mediated induction of the IL-2R alpha gene.