Lymphotoxin-α is an autocrine growth factor for chronic lymphocytic leukemia B cells

Kulmburg, P; Radke, Marc R.; Digel, Werner

doi:10.1038/sj.leu.2400954

Cited by 11 publications

(7 citation statements)

References 13 publications

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“…TNF family members were described as key regulators of CLL cell biology. LTA/TNF-b can support the proliferation of in vitro activated CLL cells (37,38), suggesting that this pathway may also contribute to the observed TLR-induced protection from drug-induced cell death. Additional cytokines and antiapoptotic molecules may concur to the final chemoresistance effect.…”

Section: Discussionmentioning

confidence: 99%

In VitroSensitivity of CLL Cells to Fludarabine May Be Modulated by the Stimulation of Toll-like Receptors

Fonte

Apollonio

Scarfò

et al. 2013

Clinical Cancer Research

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Purpose: The emerging role of Toll-like receptors (TLR) in the pathogenesis of chronic lymphocytic leukemia (CLL) led us to ask whether TLR stimulation may protect CLL cells from drug-induced apoptosis. Experimental Design: We cultured in vitro malignant B cells freshly isolated from 44 patients with CLLs in the presence or the absence of different concentrations of fludarabine before or after 24-hour TLR stimulation with specific ligands and evaluated cell viability, apoptosis, and molecular pathways involved. Results: Heterogeneity was observed among samples. In leukemic cells from patients bearing adverse prognostic factors, TLR stimulation caused a significant increase of protection to fludarabine treatment, whereas this did not occur in the cells from patients with good prognosis. To identify novel molecular mechanisms accounting for the dichotomy of response between the two groups of patients, we conducted an apoptosis gene expression profile on leukemic cells either unstimulated or stimulated with TLR9 ligand. Strikingly, TLR9 stimulation specifically upregulated the expression of lymphotoxin-α in cells where an increased protection to fludarabine treatment was observed. Also, the expression of miR-155-3p was significantly increased after stimulation of distinct TLR in cells where fludarabine treatment was less effective. Conclusions: These results suggest that at least in a proportion of patients, in vitro sensitivity to fludarabine may be modulated by the stimulation of TLR, likely mimicking microenvironmental signals occurring in vivo. Clin Cancer Res; 19(2); 367–79. ©2012 AACR.

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Section: Discussionmentioning

confidence: 99%

In VitroSensitivity of CLL Cells to Fludarabine May Be Modulated by the Stimulation of Toll-like Receptors

Fonte

Apollonio

Scarfò

et al. 2013

Clinical Cancer Research

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“…Another potential mechanism by which LTA could participate in autoimmunity is by the direct activation of B cells participating in the disease process. LTA is an autocrine growth factor for B lymphocytes and has been shown to enhance normal memory B cell responses (27,(51)(52)(53)(54)(55). These functions have been attributed partially to signaling through TNF-RI, which is activated by soluble LTA (56).…”

Section: Discussionmentioning

confidence: 99%

A Role for Lymphotoxin in Primary Sjögren’s Disease

Shen

Suresh

et al. 2010

The Journal of Immunology

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The etiology of salivary gland injury in primary Sjögren’s disease is not well understood. We have previously described a mouse model of Sjögren’s disease, IL-14α transgenic (IL14αTG) mice, which reproduces many of the features of the human disease. We now demonstrate a critical role for lymphotoxin α (LTA) in the pathogenesis of Sjögren’s disease in IL14αTG mice. IL14αTG mice express LTA mRNA in their salivary glands and spleen and produce soluble LTA protein in their salivary secretions. When IL14αTG mice were crossed with LTA−/− mice, the IL14αTG.LTA−/− mice retained normal salivary gland secretions and did not develop either lymphocytic infiltration of their salivary glands or secondary lymphomas. However, both IL14αTG and IL14αTG.LTA−/− mice produced similar amounts of IFN-α and had similar deposition of autoantibodies in their salivary glands. Both IL14α and IL14α/LTA−/− mice had similar B cell responses to T-dependent and T-independent Ags, L-selectin expression, and expression of RelA, RelB, and NF-κB2 in their spleens. These studies suggest that LTA plays a critical role in the local rather than systemic inflammatory process of Sjögren’s disease. Furthermore, local production of soluble LTA in the salivary glands of IL14αTG mice is necessary for the development of overt Sjögren’s disease. Autoantibody deposition alone is not sufficient to produce salivary gland dysfunction. We also demonstrate that LTA is increased in the salivary gland secretions and sera of patients with Sjögren’s disease, further strengthening the biological relevance of the IL14αTG model to understanding the pathogenesis of human disease.

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“…LT␣ promotes inflammatory and chemoattractant responses (46 -48) and B cell proliferation (49). LT␣ is also involved with CD8 ϩ T cell activation (50).…”

Section: Discussionmentioning

confidence: 99%

Loss of Lymphotoxin-α but Not Tumor Necrosis Factor-α Reduces Atherosclerosis in Mice

Schreyer

Vick

LeBoeuf

2002

Journal of Biological Chemistry

134

102

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Inflammatory processes are involved with all phases of atherosclerotic lesion growth. Tumor necrosis factor-␣ (TNF␣) is an inflammatory cytokine that is thought to contribute to lesion development. Lymphotoxin-␣ (LT␣) is also a proinflammatory cytokine with homology to TNF␣. However, its presence or function in lesion development has not been investigated. To study the role of these molecules in atherosclerosis, the expression of these cytokines in atherosclerotic lesions was examined. The presence of both cytokines was observed within aortic sinus fatty streak lesions. To determine the function of these molecules in regulating lesion growth, mice deficient for TNF␣ or LT␣ were examined for induction of atherosclerosis. Surprisingly, loss of TNF␣ did not alter lesion development compared with wild-type mice. This brings doubt to the generally held concept that TNF␣ is a "proatherogenic cytokine." However, LT␣ deficiency resulted in a 62% reduction in lesion size. This demonstrates an unexpected role for LT␣ in promoting lesion growth. The presence of LT␣ was observed in aortic sinus lesions suggesting a direct role of LT␣ in modulating lesion growth. To determine which receptor mediated these responses, diet-induced atherosclerosis in mice deficient for each of the TNF receptors, termed p55 and p75, was examined. Results demonstrated that loss of p55 resulted in increased lesion development, but loss of p75 did not alter lesion size. The disparity in results between ligand-and receptor-deficient mice suggests there are undefined members of the TNF ligand and receptor signaling pathway involved with regulating atherogenesis.Inflammatory processes are an integral component to atherosclerotic lesion development. Cytokine-mediated proinflammatory responses such as endothelial cell activation and leukocyte recruitment are thought to positively contribute to the atherogenic process. One of the best-studied proinflammatory cytokines is tumor necrosis factor-␣ (TNF␣) 1 that is expressed in both human and rodent atherosclerotic plaques (1-5). However, the physiological role of TNF ligand and receptor family members in the atherogenic process remains unclear.TNF␣ and lymphotoxin-␣ (LT␣) are two predominant members of the TNF ligand family. Their structural genes are located on human chromosome 6 within the major histocompatibility complex (6). TNF␣ and LT␣ proteins are structurally similar and display 50% amino acid homology (7). TNF␣ is first synthesized as a type II transmembrane protein and is subsequently cleaved to form circulating homotrimeric TNF␣ (8). TNF␣ is synthesized primarily by activated macrophages (9), although under appropriate stimulation other cells can express this cytokine (10 -12). TNF␣ influences the function of macrophages, smooth muscle cells, and endothelial cells (13), which are major cell types observed in plaques. LT␣ is synthesized primarily by activated T and B lymphocytes (6, 7) and is also found in the circulation as a homotrimer. Unlike TNF␣, membrane-bound homotrimeric LT␣ has not been o...

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Lymphotoxin-α is an autocrine growth factor for chronic lymphocytic leukemia B cells

Abstract: Lymphotoxin-alpha (LT),

Cited by 11 publications

References 13 publications

In VitroSensitivity of CLL Cells to Fludarabine May Be Modulated by the Stimulation of Toll-like Receptors

In VitroSensitivity of CLL Cells to Fludarabine May Be Modulated by the Stimulation of Toll-like Receptors

A Role for Lymphotoxin in Primary Sjögren’s Disease

Loss of Lymphotoxin-α but Not Tumor Necrosis Factor-α Reduces Atherosclerosis in Mice

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