Toll-like receptors in lymphoid malignancies: Double-edged sword

Harsini, Sara; Beigy, Maani; Akhavan-Sabbagh, Mahsa; Rezaei, Nima

doi:10.1016/j.critrevonc.2013.08.010

Cited by 25 publications

(17 citation statements)

References 233 publications

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“…26,27 Nevertheless, emerging evidence suggests that TLR may also exert a direct effect on tumor cells and may regulate tumor progression. 28,29 For example, TLR ligands induce CLL cell viability and chemoresistance in a proportion of cases.19 Furthermore, the unabated stimulation through TLR and/or IL-1R pathways accelerates leukemia progression in a mouse model of CLL. 19,30,31 Recent studies suggest a role for microenvironmental interactions in the natural history of SMZL.…”

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confidence: 99%

Toll-like receptor stimulation in splenic marginal zone lymphoma can modulate cell signaling, activation and proliferation

et al. 2015

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© F e r r a t a S t o r t i F o u n d a t i o nadaptor molecule MyD88 connects distinct TLRs to proximal IRAK kinases which then trigger a cascade of phosphorylation events, eventually leading to MAPK and IKK activation and the induction of specific transcriptional programs including that of the NF-κB complex. 16 With all the above in mind, we herein aimed at characterizing TLR expression and function in SMZL, in order to assess the potential impact of TLR signaling on the biology of this disease. Methods Cell purificationBlood and tissue samples were obtained from SMZL patients after informed consent as part of a study (ViVi-NHL) approved by the institutional ethics committee. SMZL cells were negatively selected and purified using a B-cell enrichment kit (RosetteSep; StemCell Technologies) following the manufacturer's instructions. Normal B cells were purified by negative selection (EasySep; StemCell Technologies) from buffy coats. Preparations were virtually devoid of NK cells, T-lymphocytes and monocytes.In 19 SMZL cases, total peripheral blood mononuclear cells (PBMC) were isolated by Ficoll gradient centrifugation without further purification (the percentage of CD19 + cells in these cases is reported in Online Supplementary Table S1). In all cases, subsequent flow cytometric analyses were performed after gating on CD19+ cells. TLR expression analysisSMZL cells were analyzed either at the time of blood withdrawal or after thawing. The analysis was performed by flow cytometry using the following antibodies: anti-TLR1 and anti-TLR7 (AbCam); anti-TLR2 (Invitrogen); anti-TLR6 and anti-TLR10 (IMGENEX); anti-TLR8 (DENDRITICS), and anti-TLR9 (eBiosciences). The BD Cytofix/Cytoperm reagent was used for the intracellular staining of TLR7, TLR8 and TLR9. Antibodies against IgD, IgM, CD38 and CD19 were used to detect normal MZ B cells in spleen samples, as previously described. 7-AminoActinomycin D (7-AAD, BD Pharmingen™) was used for the exclusion of nonviable cells in flow cytometric assays. All flow cytometric analyses were performed on a FC-500 (Beckman Coulter) or on a FACSAria II (Becton Dickinson). Cell culture and functional studiesSMZL cells were either unstimulated or stimulated with specific TLR ligands (Online Supplementary Methods). Collection was performed either after 24 hours for CD86 (BD Pharmingen) and CD25 (Beckman Coulter) flow cytometry analysis, or after 48 hours to assess cell proliferation (Ki67 staining, BD Biosciences), apoptosis (Annexin V and Propidium Iodide, Bender Med Systems) and viability (CellTiter-Glo Luminescent Cell Viability Assay, Promega). The IRAK1/4 inhibitor I (Sigma) was used at the concentration of 3 μM 30 minutes before TLR stimulation. The MyD88 inhibitory peptide and control peptide (Novus Biologicals) were used at the concentration of 100 μM. Molecular studiesi. Immunogenetic analysis. PCR amplification and sequence analysis of IGHV-IGHD-IGHJ gene rearrangements was performed as previously described. 20 ii. Qualitative assessment of TLR1-10 and TIR8 expression b...

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confidence: 99%

Toll-like receptor stimulation in splenic marginal zone lymphoma can modulate cell signaling, activation and proliferation

et al. 2015

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“…Certain cases of ALL have been reported in individuals with Weaver syndrome [38]. As certain diseases, such as ALL linking to TLR signaling, have also been reported [39], LRRC33, as a member of the LRR family, may have a global role in immunity and inflammation. AUTHORSHIP R.Y.…”

Section: Discussionmentioning

confidence: 99%

Epigenetically modulated LRRC33 acts as a negative physiological regulator for multiple Toll-like receptors

Mei

et al. 2014

Journal of Leukocyte Biology

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The members of a LRR family play crucial roles in the activation of innate and adaptive immune responses. We reported previously that LRRC33, a transmembrane protein of the LRR family, might potentially affect TLR-mediated activity. Here, we demonstrate that LRRC33 is a negative physiological regulator for multiple TLRs. Lrrc33(-/-) and Lrrc33(+/-) mice were more susceptible to TLR ligand challenges. The macrophages and DCs from Lrrc33(-/-) mice produced more proinflammatory cytokines than those of WT mice through increased activation of MAPK and NF-κB. Silencing LRRC33 also promoted multiple TLR-mediated activation in human moDCs. Notably, LRRC33 expression could be down-regulated by TLR ligands LPS, poly I:C, or PGN through H3K4me3 and H3K27me3 modification. In LPS-conditioned moDCs, reduced enrichment of H3K4me3 and increased H3K27me3 could be observed at the promoter region of LRRC33. Furthermore, silencing H3K4me3-associated factors MLL and RBBP5 not only decreased the enrichment of H3K4me3 but also down-regulated expression of LRRC33, whereas the expression of LRRC33 was up-regulated after silencing H3K27me3-associated factors EZH2 and EED. Thus, our results suggest that LRRC33 and TLRs may form a negative-feedback loop, which is important for the maintenance of immune homeostasis.

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“…Similarly, activation of the tolllike receptor pathway caused by antigens and microbes present in the microenvironment has been shown to activate lymphoma cell growth [39,40]. Toll-like receptor signaling plays a role in subtypes of diffuse large B-cell lymphoma, splenic marginal zone lymphoma, and lymphoplasmacytic lymphoma, and mutations in the MyD88 pathway appear to be particularly important in lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia [41][42][43]. Additional support is provided by immune cells to the malignant cells through the secretion of cytokines.…”

Section: Composition Of the Tumor Microenvironmentmentioning

confidence: 97%