CpG oligodeoxynucleotide CpG-685 upregulates functional interleukin-21 receptor on chronic lymphocytic leukemia B cells through an NF-κB mediated pathway

Abstract

CpG oligodeoxynucleotides (ODNs) upregulate the interleukin-21 receptor (IL21R) and enhance IL-21-mediated cytotoxicity in chronic lymphocytic leukemia (CLL) B cells. We demonstrate that treatment of CLL B cells with the ODN CpG-685 leads to increased IL21R expression, and that this increased expression enhances the effects of IL-21 treatment as evidenced by increased phosphorylation of JAK1, STAT1, and STAT3, as compared to IL-21 treatment without prior CpG stimulation. Induction of IL21R by CpG-685 also enhanced IL-21-mediated cytotoxicity. The mechanism by which CpG ODNs upregulate IL21R has not been elucidated, although IL21R regulation in T cells has been shown to be linked to T cell receptor-induced Sp1 binding to the IL21R promoter. Here, we demonstrate that luciferase reporter constructs containing the Sp1 binding site have increased basal luciferase activity compared to constructs lacking the Sp1 binding site, but fail to increase luciferase activity with CpG-685 stimulation in CLL B cells. By treating CLL cells with an NF-κB inhibitor, we inhibit the CpG ODN-mediated induction of IL21R, thus demonstrating that CpG-685 upregulates IL21R through an NF-κB mediated pathway. These findings suggest an alternative mechanism for induction of IL-21 receptor in CLL B cells and provide a basis for creation of future combination therapies.

Clinico-Biological Implications of Modified Levels of Cytokines in Chronic Lymphocytic Leukemia: A Possible Therapeutic Role

“…The CpG ODN-mediated induction of IL21R was diminished after the use of an NF-κB inhibitor, demonstrating that CpG-685 boosts IL21R via an NF-κB-mediated mechanism. These data indicate an alternative system for the stimulation of IL-21R in B-CLL cells and offer a basis for the conception of new combination treatments [60].…”

“…IL-21 Antitumoral Increased apoptosis [55][56][57][58][59][60] Increased proliferation of cytotoxic T cells [61,62] IL-22 Protumoral Stimulation of STAT3 [63][64][65][66] Reduced apoptosis [63][64][65][66] IL-23 Protumoral Unclear [67] TNF-alpha Protumoral Increased proliferation [68,69] STAT: Signal Transducer and Activator of Transcription; INKT: invariant Natural Killer; VEGF: Vascular Endothelial Cell Growth Factor; BCL-2: B-cell lymphoma 2; NK: Natura Killer; IL: Interleukin; TNF: Tumour Necrosis Factor.…”

The BTK Inhibitor ARQ 531 Targets Ibrutinib-Resistant CLL and Richter Transformation

“…BTK activation has been shown to increase NF-κB activity and thus CLL cell activation, (30) events which can be blocked by ibrutinib. (14) To determine whether ARQ 531 similarly affects NF-κB target genes, we performed real time PCR in primary CLL cells following treatment with ARQ 531 and ibrutinib.…”

IL-21R functions as an oncogenic factor and is regulated by the lncRNA MALAT1/miR-125a-3p axis in gastric cancer

“…Interleukin (IL)-21, identified as a member of the IL-2 family, is involved in biological activities in cancer and autoimmunity by binding to its receptor, IL-21R ( 7 ), which is highly expressed in hematological malignancies ( 8 , 9 ) and enhances the aggressiveness of follicular lymphoma ( 10 ). IL-21/IL-21R axis results in the pathogenesis of leukemia and large cell lymphoma through activation of the JAK/STAT signaling pathway ( 11 , 12 ), indicating that IL-21R may present a potential therapeutic target for cancer therapy.…”