Abstract
Interleukin-7 (IL-7) is an essential cytokine for lymphocyte growth that has the potential for promoting immune reconstitution. This feature makes IL-7 an ideal candidate for therapeutic development. As with other cytokines, signaling through the IL-7 receptor induces the JAK/STAT pathway. However, the broad scope of IL-7 regulatory targets likely necessitates the use of other signaling components whose identities remain poorly defined. To this end, we used an IL-7 dependent T-cell line to examine how expression of the glycolytic enzyme, Hexokinase II (HXKII) was regulated by IL-7 in a STAT5-independent manner. Our studies revealed that IL-7 promoted the activity of JNK (Jun N-terminal Kinase), and that JNK, in turn, drove the expression of JunD, a component of the Activating Protein 1 (AP-1) transcription factors. Gel shifts showed that the AP-1 complex induced by IL-7 contained JunD but not c-Fos or c-Jun. Inhibition of JNK/JunD blocked glucose uptake and HXKII gene expression, indicating that this pathway was responsible for promoting HXKII expression. Because others had shown that JunD was a negative regulator of cell growth, we performed a bioinformatics analysis to uncover possible JunD-regulated gene targets. Our search revealed that JunD could control the expression of proteins involved in signal transduction, cell survival and metabolism. One of these growth promoters was the oncogene, Pim-1. Pim-1 is an IL-7-induced protein that was inhibited when the activities of JNK or JunD were blocked, showing that in IL-7 dependent T-cells JunD can promote positive signals transduced through Pim-1. This was confirmed when the IL-7-induced proliferation of CD8 T-cells was impaired upon JunD inhibition. These results show that engagement of the IL-7 receptor drives a signal that is more complex than the JAK/STAT pathway, activating JNK and JunD to induce rapid growth stimulation through the expression of metabolic and signaling factors like HXKII and Pim-1.
Highlights
Interleukin-7 (IL-7) plays a major role in lymphocyte survival, development and proliferation [1]
Using an IL-7 dependent T-cell line, D1, and primary T-cells, we reported that Hexokinase II (HXKII) gene expression was regulated by an IL-7 signal [39]
We found that the IL-4-induced gene expression and glucose uptake in nucleofected cells was not affected by the Y449 mutation and that cells were comparable to those incubated with IL-7, suggesting that these events were STAT5-independent (Fig. 1A)
Summary
Interleukin-7 (IL-7) plays a major role in lymphocyte survival, development and proliferation [1]. Because of its importance as a lymphocyte growth factor, IL-7 has potential use as a therapeutic agent in cancer therapy [2], bone marrow transplantation [3] and treatment of infectious diseases like sepsis [4] and HIV [5]. IL-7 is a 25 kDa protein that is not produced by lymphocytes but was discovered as a product of a thymic stromal cell line [6]. Tissues that produce IL-7 include the generative lymphoid organs [7,8]; the regulation of IL-7 production remains unclear but could be induced in nonlymphoid tissues upon infection [9]. Upon binding of IL-7, the two receptor chains heterodimerize and initiate signaling mediated through receptor-associated kinases, Janus kinases, Jak1/Jak, which phosphorylate and activate the transcription factor, STAT5a/b [1]. The most recent biological information on IL-7 signal transduction focuses on the JAK/
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