Differential Effects of Interleukin-2 and Interleukin-15 versus Interleukin-21 on CD4+ Cutaneous T-Cell Lymphoma Cells

Abstract

In this study, we compared the effects of interleukin-2 (IL-2), IL-15, and IL-21 on gene expression, activation of cell signaling pathways, and functional properties of cells derived from CD4+ cutaneous T-cell lymphoma (CTCL). Whereas both IL-2 and IL-15 modulated, in a CTCL cell line, the expression of >1,000 gene transcripts by at least 2-fold, IL-21 up-regulated <40 genes. All three cytokines induced tyrosine phosphorylation of Jak1 and Jak3 in CTCL cell lines and native leukemic (Sezary) cells. However, only IL-2 and IL-15 strongly activated signal transducers and activators of transcription 5, phosphoinositide 3-kinase/Akt, and mitogen-activated protein/ extracellular signal-regulated kinase (ERK) kinase/ERK signaling pathways in the cell lines and mitogen-primed native cells. In contrast, IL-21 selectively activated signal transducers and activators of transcription 3. Whereas all three cytokines protected CTCL cells from apoptosis, only IL-2 and IL-15 promoted their proliferation. The effects of the cytokine stimulation were Jak3 kinase-and Jak1 kinase-dependent. These findings document the vastly different effect of IL-2 and IL-15 versus IL-21 on CTCL cells. They also suggest two novel therapeutic approaches to CTCL and, possibly, other CD4+ T-cell lymphomas: inhibition of the Jak1/Jak3 kinase complex and, given the known strong immunostimulatory properties of IL-21 on CD8+ T, natural killer, and B cells, application of this cytokine to boost an immune response against malignant CD4+ T cells. [Cancer Res 2008;68(4):1083-91]

Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1)

“…Treatment of ALKϩTCL SUDHL-1 cells with inhibitors of several kinases known to be down-stream of NPM/ALK-rapamycin (mTORC1 inhibitor), wortmanin (PI-3K), U0126 (MEK1/2), or Jak3 inhibitor-all used at the preselected profoundly inhibitory doses, as shown by us previously (15,16,18,20), had no detectable impact on CD274 expression either on the protein or mRNA level (Fig. S3).…”

STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma

“…22 As these cytokines activate STAT5 in normal T cells, we investigated IL-2-dependent induction of miR-155 was also observed in primary T cells obtained from the blood of SS patients (Fig. 4B, P3 and P4) and sorted into CD4 + /CD26 − (malignant) and CD4 + / CD26 + (non-malignant) populations.…”

“…16 The etiology of CTCL is unknown, but evidence suggests that the IL-2 receptor (IL-2R) complex and the associated Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) play a key role in the disease pathogenesis. Thus, malignant T cells display a constitutive expression of the highaffinity IL-2R complex [consisting of IL-2Rα (CD25), IL-2Rβ (CD122) and IL-2Rγ (CD132)] 19-21 and respond to IL-2 family cytokines (IL-2, 22 IL-7, 23,24 IL-15, 25 and IL-21 22 ) by activation of The present investigation was undertaken to address the abnormal expression and function of the oncogenic miR-155 in CTCL. We provide the first evidence that the miR-155 host gene BIC is a transcriptional target of STAT5, and that miR-155 is involved in proliferation of malignant T cells, suggesting that the STAT5/BIC/miR-155 pathway is a putative target for therapy.…”

Cutaneous T‐cell lymphoma: 2011 update on diagnosis, risk‐stratification, and management

“…Not surprisingly then, pharmacologic inhibition of STAT3 promotes apoptosis in CTCL [77,[80][81][82]. Cytogenetic gains involving STAT5A and STAT5B or their activation in response to cytokines present within the tumor microenvironment suggests a pathogenic role for other STATs [83][84][85].…”