Signal transduction mechanisms of CD137 ligand in human monocytes

Söllner, Liane; Shaqireen, D; Wu, Ju Ting; Schwarz, Herbert

doi:10.1016/j.cellsig.2007.04.014

Cited by 32 publications

(25 citation statements)

References 37 publications

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“…The signal transduction initiated by CD137L has only partly been studied and involves nuclear factor-kB (NF-jB), phosphatidylinositol-3-kinase/Akt and mitogen-activated protein kinase, involving c-Jun-N-terminal kinase (JNK), p38 and extracellular signal-regulated kinase (Saito et al, 2004;Sollner et al, 2007;Kim et al, 2011). Except for a casein kinase recognition site, CD137L seems to lack conserved motifs for signal transduction in its short cytoplasmic domain (Watts et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

CD137 ligand signalling induces differentiation of primary acute myeloid leukaemia cells

et al. 2014

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SummaryCD137 ligand (CD137L), a member of the tumour necrosis factor family, is expressed as a cell surface molecule. Engagement of CD137L on haematopoietic progenitor cells induces monocytic differentiation, and in peripheral monocytes CD137L signalling promotes differentiation to mature dendritic cells. We hypothesized that CD137L signalling would also induce differentiation in transformed myeloid cells. Here we show that recombinant CD137 protein, which crosslinks CD137L and initiates reverse CD137L signalling in myeloid cells, induces morphological changes (adherence, spreading), loss of progenitor markers (CD117), expression of maturation markers (CD11b, CD13) and secretion of cytokines that are indicative of myeloid differentiation. Under the influence of CD137L signalling, acute myeloid leukaemia (AML) cells acquired expression of co-stimulatory molecules (CD80, CD86, CD40), the dendritic cell marker CD83 and dendritic cell activities, enabling them to stimulate T cells. CD137L signalling induced differentiation in 71% (15 of 21) of AML samples, irrespective of French-American-British classification and CD137L expression level. However, the type of response varied with the AML subtype and patient sample. In summary, this study demonstrated that CD137L signalling induced differentiation in malignant cells of AML patients, and suggests that it may be worthwhile to investigate treatment with recombinant CD137 protein as a potential novel therapeutic approach for AML.

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Section: Discussionmentioning

confidence: 99%

CD137 ligand signalling induces differentiation of primary acute myeloid leukaemia cells

et al. 2014

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“…39,40 Reverse signaling through the ligands offers the advantage of rapid feedback and fine-tuning of biological responses. However, limited information is currently available on the signaling mechanism of CD137L induced by CD137.…”

Section: Discussionmentioning

confidence: 99%

CD137 (4–1BB) Deficiency Reduces Atherosclerosis in Hyperlipidemic Mice

et al. 2010

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Background— The tumor necrosis factor receptor superfamily, which includes CD40, LIGHT, and OX40, plays important roles in atherosclerosis. CD137 (4-1BB), a member of the tumor necrosis factor receptor superfamily, has been reported to be expressed in human atherosclerotic lesions. However, limited information is available on the precise role of CD137 in atherosclerosis and the effects of blocking CD137/CD137 ligand signaling on lesion formation. Methods and Results— We generated CD137-deficient apolipoprotein E–knockout mice ( ApoE −/− CD137 −/− ) and LDL-receptor–knockout mice ( Ldlr −/− CD137 −/− ) to investigate the role of CD137 in atherogenesis. The deficiency of CD137 induced a reduction in atherosclerotic plaque lesions in both atherosclerosis mouse models, which was attributed to the downregulation of cytokines such as interferon-γ, monocyte chemoattractant protein-1, and tumor necrosis factor-α. CD137 signaling promoted the production of inflammatory molecules, including monocyte chemoattractant protein-1, interleukin-6, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1, in endothelial cells. Stimulation of CD137 ligand signaling activated monocytes/macrophages and augmented the production of proinflammatory cytokines in atherosclerotic vessels. Conclusions— CD137/CD137 ligand signaling plays multiple roles in the progression of atherosclerosis, and thus, blockade of this pathway is a promising therapeutic target for the disease.

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“…Although 4-1BBL delivers costimulatory signals to T cells for proliferation and survival by binding its receptor 4-1BB, 4-1BBL also transmits positive or negative signals to APCs depending on the antigen-specific T cell response. These 4-1BBL-induced reverse signals involve several molecules known to play roles in receptor-mediated signal transduction (29). For example, protein-tyrosine kinases p38 MAPK, ERK1, ERK2, MAPK/ERK kinase (MEK), phosphatidylinositol 3-kinase, and cAMP-dependent protein kinase are all involved in 4-1BBL-mediated signaling (29).…”

Section: Discussionmentioning

confidence: 99%

The Structure of the Trimer of Human 4-1BB Ligand Is Unique among Members of the Tumor Necrosis Factor Superfamily

Won

Cha

Byun

et al. 2010

Journal of Biological Chemistry

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Binding of the 4-1BB ligand (4-1BBL) to its receptor, 4-1BB, provides the T lymphocyte with co-stimulatory signals for survival, proliferation, and differentiation. Importantly, the 4-1BB-4-1BBL pathway is a well known target for anti-cancer immunotherapy. Here we present the 2.3-Å crystal structure of the extracellular domain of human 4-1BBL. The ectodomain forms a homotrimer with an extended, three-bladed propeller structure that differs from trimers formed by other members of the tumor necrosis factor (TNF) superfamily. Based on the 4-1BBL structure, we modeled its complex with 4-1BB, which was consistent with images obtained by electron microscopy, and verified the binding site by site-directed mutagenesis. This structural information will facilitate the development of immunotherapeutics targeting 4-1BB.

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Signal transduction mechanisms of CD137 ligand in human monocytes

Cited by 32 publications

References 37 publications

CD137 ligand signalling induces differentiation of primary acute myeloid leukaemia cells

CD137 ligand signalling induces differentiation of primary acute myeloid leukaemia cells

CD137 (4–1BB) Deficiency Reduces Atherosclerosis in Hyperlipidemic Mice

The Structure of the Trimer of Human 4-1BB Ligand Is Unique among Members of the Tumor Necrosis Factor Superfamily

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