Abstract
IL-24, also known as melanoma differentiation antigen 7 (mda-7), is a member of the IL-10 family of cytokines and is mainly produced by Th2 cells as well as by activated monocytes. Binding of IL-24 to either of its two possible heterodimeric receptors IL-20R1/IL-20R2 and IL-22R/IL-20R2 activates STAT3 and/or STAT1 in target tissues such as lung, testis, ovary, keratinocytes and skin. To date, the physiological properties of IL-24 are still not well understood but available data suggest that IL-24 affects epidermal functions by increasing proliferation of dermal cells. In stark contrast to its “normal” and physiological behaviour, IL-24 has been reported to selectively and efficiently kill a vast variety of cancer cells, especially melanoma cells, independent of receptor expression and Jak-STAT signalling. These intriguing properties have led to the development of adenovirally-expressed IL-24, which is currently being evaluated in clinical trials. Using three different methods, we have analysed a large panel of melanoma cell lines with respect to IL-24 and IL-24 receptor expression and found that none of the investigated cell lines expressed sufficient amounts of functional receptor pairs and therefore did not react to IL-24 stimulation with Jak/STAT activation. Results for three cell lines contrasted with previous studies, which reported presence of IL-24 receptors and activation of STAT3 following IL-24 stimulation. Furthermore, evaluating four different sources and modes of IL-24 administration (commercial recombinant IL-24, bacterially expressed GST-IL-24 fusion protein, IL-24 produced from transfected Hek cells, transiently over-expressed IL-24) no induction or increase in cell death was detected when compared to appropriate control treatments. Thus, we conclude that the cytokine IL-24 itself has no cancer-specific apoptosis-inducing properties in melanoma cells.
Highlights
Interleukin (IL) -24, a member of the IL-10 family of cytokines, has been discovered in 1995 by subtraction hybridization following ‘‘differentiation therapy’’ of melanoma cells: through treatment with IFN-b and a protein kinase C inhibitor neoplastic melanoma cells terminally differentiate and lose their proliferative capacity
The melanoma cell lines A375, MeWo, and Wm35 did not react to IL-24 previous studies had reported that IL-24 led to STAT3 activation in these cells [28,29]
IL-24 produced from transfected human embryonic kidney cells (Hek) cell supernatants, which will be discussed in more detail below, induced phosphorylation of STAT3 in HaCaT cells but not in any of the melanoma cell lines
Summary
Interleukin (IL) -24 (mda-7), a member of the IL-10 family of cytokines (together with IL-10, -19, -20, -22, and -26), has been discovered in 1995 by subtraction hybridization following ‘‘differentiation therapy’’ of melanoma cells: through treatment with IFN-b and a protein kinase C inhibitor (mezerein) neoplastic melanoma cells terminally differentiate and lose their proliferative capacity. Thereafter it has been demonstrated that IL-24 is a typical cytokine as it binds to specific receptors, it is secreted, it activates the JAK/STAT signaling pathway and it can modulate growth characteristics of responsive cells [7,8,9,10]. On receptor-expressing cells, IL-24 activates the JAK-STAT pathway, shown by phosphorylation of STAT3 [11,12]. The cellular targets of IL-24-activated STAT3 transcription factors and the physiological role of this IL-24-induced signalling remain to be clarified
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