Expression of functional toll-like receptors by B-chronic lymphocytic leukemia cells

Grandjenette, Cindy; Kennel, Anne; Fauré, G; Béné, Marie C.; Feugier, Pierre

doi:10.3324/haematol.10975

Cited by 42 publications

(31 citation statements)

References 10 publications

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“…TLRs play a key role in the response of immune cells to patterned antigens present in microorganisms, including single-stranded RNA (TLR7 and TLR8) and CpG-enriched DNA (TLR9) (8). CLL cells express TLR1, 2, 6, 7 and 9 but not TLR8 (9–13). Treatment of CLL cells with synthetic TLR ligands induces CLL proliferation (10).…”

Section: Introductionmentioning

confidence: 98%

Inhibition of Type 4 Cyclic Nucleotide Phosphodiesterase Blocks Intracellular TLR Signaling in Chronic Lymphocytic Leukemia and Normal Hematopoietic Cells

Tan

Watkins

Freeman

et al. 2015

The Journal of Immunology

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A subset of chronic lymphocytic leukemia (CLL) B cell receptors (BCRs) interact with antigens expressed on apoptotic cells, suggesting that CLL BCRs have the potential to internalize apoptotic cell RNA or DNA-containing fragments with resultant activation of TLR7 or TLR9, respectively. By blocking cAMP degradation, type 4 cyclic nucleotide phosphodiesterase (PDE4) inhibitors activate cAMP-mediated signaling and induce apoptosis in CLL cells. Here we show that autologous irradiated leukemic cells induce proliferation in CLL cells and that such proliferation is blocked by a TLR7/8/9 inhibitor, by DNase and by the PDE4 inhibitor rolipram. Rolipram also inhibited CLL cell proliferation induced by synthetic TLR7 and TLR9 agonists, as well as TLR agonist-induced costimulatory molecule expression and TNF-α (but not IL-6 or IL-10) production. While treatment with a TLR9 agonist protected immunoglobulin heavy chain variable region (IGHV) unmutated, but not mutated, CLL cells from apoptosis, PDE4 inhibitors augmented apoptosis in both subtypes, suggesting that cAMP-mediated signaling may abrogate a TLR9-mediated survival signal in prognostically unfavorable IGHV-unmutated CLL cells. Rolipram inhibited both TLR7/8 and TLR9-induced IRF5 and NF-κB p65 nuclear translocation. PDE4 inhibitors also blocked TLR signaling in normal human immune cells. In peripheral blood whole mononuclear cells (PBMC) and CD14-positive monocytes, PDE4 inhibitors blocked IFN-α or TNF-α (but not IL-6) production, respectively, following stimulation with synthetic TLR agonists or RNA-containing immune complexes. These results suggest that PDE4 inhibitors may be of clinical utility in CLL or autoimmune diseases that are driven by TLR-mediated signaling.

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Section: Introductionmentioning

confidence: 98%

Inhibition of Type 4 Cyclic Nucleotide Phosphodiesterase Blocks Intracellular TLR Signaling in Chronic Lymphocytic Leukemia and Normal Hematopoietic Cells

Tan

Watkins

Freeman

et al. 2015

The Journal of Immunology

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“…[10][11][12] TLR9 is also expressed in a wide variety of B-cell leukemias and lymphomas, but CpG oligonucleotides (ODNs) may have varying effects, depending on the specific malignancy. 10,[13][14][15][16] CpG ODNs have been clinically studied as agents to induce or augment antitumor immunity in several tumor types, including B-cell NHL. 17,18 Although these trials have shown limited benefit, CpG ODNs have been relatively well tolerated, suggesting that they may be safely combined with other antitumor agents.…”

Section: Introductionmentioning

confidence: 99%

Mantle cell lymphoma activation enhances bortezomib sensitivity

Brennan

Meade

Wang

et al. 2010

Blood

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IntroductionMantle cell lymphoma (MCL) is an aggressive, incurable B-cell malignancy that makes up 5% to 10% of non-Hodgkin lymphoma (NHL) cases. 1 Patients with MCL typically present with extensive lymph node involvement as well as extranodal dissemination within the spleen, bone marrow, and gastrointestinal tract. Treatment with conventional cytotoxic agents produces high initial response rates, but the outcome of patients with MCL remains among the poorest of all NHL subtypes with a median overall survival of 3 to 4 years. 2,3 Relapse after initial disease control suggests that a subset of cells can survive treatment and mediate tumor regrowth. In many cancers, specific populations of tumor cells with increased clonogenic potential have been identified and referred to as tumor initiating cells or cancer stem cells (CSCs). 4 Similar to normal adult stem cells, CSCs may be quiescent and resistant to a wide variety of cytotoxic agents. [5][6][7] However, few strategies have been developed to overcome CSC quiescence and chemoresistance.Normal B cells can be activated by antigen binding to the B-cell receptor as well as several antigen-independent processes. Toll-like receptors (TLRs) are innate immune receptors that recognize a diverse range of pathogen-derived microbial molecules, and several TLRs are expressed during normal B-cell development. 8,9 In humans TLR9 is expressed in B cells and plasmacytoid dendritic cells and recognizes unmethylated cytosine-phosphate-guanosine (CpG) motifs that mimic bacterial or viral DNA to induce cellular activation and differentiation. [10][11][12] TLR9 is also expressed in a wide variety of B-cell leukemias and lymphomas, but CpG oligonucleotides (ODNs) may have varying effects, depending on the specific malignancy. 10,[13][14][15][16] CpG ODNs have been clinically studied as agents to induce or augment antitumor immunity in several tumor types, including B-cell NHL. 17,18 Although these trials have shown limited benefit, CpG ODNs have been relatively well tolerated, suggesting that they may be safely combined with other antitumor agents. We studied the effects of CpG ODNs in MCL cells and found that they activate a minor population of relatively quiescent cells with increased clonogenic potential. Furthermore, CpG ODNs induce plasmacytic differentiation of MCL cells and enhance sensitivity to the proteosome inhibitor bortezomib. Cells were cultured in complete media consisting of RPMI 1640, 2mM L-glutamine, 50 U/mL penicillin, 50 g/mL streptomycin, and 10% fetal bovine serum. Clonogenic growth was evaluated by plating 1000 cells/mL in 1 mL of 1.2% methylcellulose, 30% fetal bovine serum, 1% bovine serum albumin, 10 Ϫ4 M 2-mercaptoethanol, and 2mM L-glutamine. Samples were plated in triplicate onto 35-mm 2 tissue culture dishes and incubated at 37°C and 5% CO 2 . Colonies consisting of more than 40 cells were scored between 7 and 10 days with an inverted microscope. Serial replating was performed by washing plates with complete media and resuspending cells in the original vol...

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“…Most of the research in B-chronic lymphocyte leukaemia (B-CLL) has concentrated on TLR7 and TLR9, as preliminary data suggested that they are the two main TLRs expressed on CLL cells (Decker et al, 2002;Spaner et al, 2006;Grandjenette et al, 2007;Muzio et al, 2009). TLR7 and TLR9 agonists may indirectly clear CLL cells by enhancing the activity of natural killer and tumour-reactive T cells, or by altering the tumour microenvironment and inhibiting angiogenesis (Spaner & Masellis, 2007).…”

Section: Activation Of Nf-jb By Lps and Cpg Dna Contributed To MM Celmentioning

confidence: 99%

Expression and function of toll‐like receptors in multiple myeloma patients: toll‐like receptor ligands promote multiple myeloma cell growth and survival via activation of nuclear factor‐κB

Zhao

Huang

et al. 2010

Br J Haematol

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SummaryToll like receptors (TLRs) are the major agents for innate immunity that recognize invading microbial products and regulate the growth of normal and malignant human B lymphocytes. Multiple myeloma (MM) is a clonal plasma cell malignancy, though the regulatory role of TLRs in MM plasma cells has been reported, the molecular mechanism remains unclear. We first compared the transcripts of TLR1 to TLR10 in MM patients and healthy donors and found that TLR2, ‐4 and ‐9 transcripts were higher in bone marrow mononuclear cells (BMMCs) from patients than those from donors; in addition the expression of TLR4 and TLR9 were higher in MM cells than normal cells as demonstrated by flow cytometric analyses. The ligands of these two TLRs were capable to promote the growth of MM cells and protect them from serum‐deprivation‐induced apoptosis but not normal plasma cells, which could be attenuated with anti‐IL6 neutralizing antibodies or blockage of NF‐κB activities. Further investigation demonstrated that these TLR ligands could trigger the nuclear translocation of NF‐κB p65 and the activated NF‐κB was sufficient to increase the expression of IL6 transcript in MM cells. These data suggested that activated NF‐κB signalling probably plays a crucial role for the ligands of TLR4 and TLR9 to promote the growth and survival of MM cells partially through IL6 autocrine.

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Expression of functional toll-like receptors by B-chronic lymphocytic leukemia cells

Cited by 42 publications

References 10 publications

Inhibition of Type 4 Cyclic Nucleotide Phosphodiesterase Blocks Intracellular TLR Signaling in Chronic Lymphocytic Leukemia and Normal Hematopoietic Cells

Inhibition of Type 4 Cyclic Nucleotide Phosphodiesterase Blocks Intracellular TLR Signaling in Chronic Lymphocytic Leukemia and Normal Hematopoietic Cells

Mantle cell lymphoma activation enhances bortezomib sensitivity

Expression and function of toll‐like receptors in multiple myeloma patients: toll‐like receptor ligands promote multiple myeloma cell growth and survival via activation of nuclear factor‐κB

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