CD40 Signaling and Plaque Instability

Schönbeck, Uwe; Libby, Peter

doi:10.1161/hh2401.101272

Cited by 506 publications

(430 citation statements)

References 142 publications

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“…[1][2][3] CD40 and CD40L are expressed on endothelial cells, vascular smooth muscle cells, mononuclear cells, and platelets, and CD40-CD40L interaction has been shown to exhibit proinflammatory and proatherogenic effects in vitro and in vivo. 4,5 In addition to the cell-associated form, CD40L also exists in a soluble, biologically active form (sCD40L), which has similar proinflammatory effects on vascular cells.…”

Section: Nteraction Of the Multipotent Immunomodulator Cd40mentioning

confidence: 99%

CD40 Ligand–Dependent Tyrosine Nitration of Prostacyclin Synthase In Vivo

Davis

Zou

2005

Circulation

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Background-Cells in human atherosclerotic lesions express the immune mediator CD40 and its ligand, CD40L, but the mechanisms and the mediators by which CD40L contributes to atherosclerosis are poorly defined. Here, we show how CD40L increases vascular inflammation and thrombosis via tyrosine nitration and inhibition of prostacyclin synthase (PGIS), an enzyme with antithrombotic, antiproliferative, and dilatory functions in the normal vasculature. Methods and Results-Exposure of cultured human aortic endothelial cells to clinically relevant concentrations of CD40L (20 to 80 ng/mL) dose-dependently increased the production of superoxide (O 2 ⅐ Ϫ ), decreased nitric oxide (NO) bioactivity, and increased PGIS nitration. Furthermore, inhibition of CD40 expression by small interfering RNA blocked the effects of CD40L on O 2 ⅐ Ϫ , NO bioactivity, and PGIS nitration, which indicates a specific effect of CD40L. In addition, either depletion of mitochondria ( 0 cells, ie, mitochondria-depleted cells, to prevent mitochondrial O 2 ⅐ Ϫ ) or adenoviral overexpression of superoxide dismutase, as well as inhibition of NO synthase, abolished the CD40L-enhanced PGIS nitration, which implies that the mitochondria might be the source of O 2 ⅐ Ϫ and thus peroxynitrite (ONOO Ϫ ). Furthermore, SQ29548, a thromboxane A 2 /prostaglandin H 2 receptor antagonist, significantly reduced CD40L-enhanced expression of intercellular adhesion molecule-1. Finally, administration of CD40L resulted in PGIS inhibition and nitration in the aortas of C57BL6 mice but less in mice overexpressing human superoxide dismutase, which suggests that ONOO Ϫ might be required for CD40L-enhanced PGIS nitration in vivo. Conclusions-We

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Section: Nteraction Of the Multipotent Immunomodulator Cd40mentioning

confidence: 99%

CD40 Ligand–Dependent Tyrosine Nitration of Prostacyclin Synthase In Vivo

Davis

Zou

2005

Circulation

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“…While extensive research is dedicated to the effect of an inflammatory reaction on obesity-related insulin resistance, little is known about the triggering pathway of inflammation during obesity. Considerable evidence implicates the proinflammatory CD40 molecule, TNF receptor superfamily member 5 (CD40) ligand (CD40L or CD154) in atherosclerosis [2][3][4], and some recent data identify CD40/CD40L as a potential contributor to inflammation associated with obesity and its metabolic complications. Soluble CD40L (sCD40L) levels are increased in obese [5,6] and type 2 diabetic [7][8][9] individuals, as well as in individuals with the metabolic (insulin resistance) syndrome [10].…”

Section: Introductionmentioning

confidence: 99%

The inflammatory receptor CD40 is expressed on human adipocytes: contribution to crosstalk between lymphocytes and adipocytes

et al. 2009

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Aims/hypothesis Obesity is associated with adipose tissue inflammation. The CD40 molecule, TNF receptor superfamily member 5 (CD40)/CD40 ligand (CD40L) pathway plays a role in the onset and maintenance of the inflammatory reaction, but has not been studied in human adipose tissue. Our aim was to examine CD40 expression by human adipocytes and its participation in adipose tissue inflammation. Methods CD40 expression was investigated in human whole adipose tissue and during adipocyte differentiation by real-time PCR, Western blot and immunohistochemistry. The CD40/CD40L pathway was studied using recombinant CD40L (rCD40L) in adipocyte culture and neutralising antibodies in lymphocyte/adipocyte co-culture. Results CD40 mRNA levels in subcutaneous adipose tissue were higher in the adipocyte than in the stromal-vascular fraction. CD40 expression was upregulated during adipocyte differentiation. Addition of rCD40L to adipocytes induced mitogen activated protein kinase (MAPK) activation, stimulated inflammatory adipocytokine production, and decreased insulin-induced glucose transport in parallel with a downregulation of IRS1 and GLUT4 (also known as SCL2A4). rCD40L decreased the expression of lipogenic genes and increased lipolysis. CD40 mRNA levels were significantly higher in subcutaneous adipose tissue than in visceral adipose tissue of obese patients and were positively correlated with BMI, and with IL6 and leptin mRNA levels. Lymphocyte/adipocyte co-culture led to an upregulation of proinflammatory adipocytokines and a downregulation of leptin and adiponectin. Physical separation of the two cell types attenuated these effects, suggesting the involvement of a cell-cell contact. Blocking the CD40/CD40L interaction with neutralising antibodies reduced IL-6 secretion from adipocytes. Conclusions/interpretation Adipocyte CD40 may contribute to obesity-related inflammation and insulin resistance. T lymphocytes regulate adipocytokine production through both the release of soluble factor(s) and heterotypic contact with adipocytes involving CD40.

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“…10 Conversely, there is potential for therapeutic activity by CD40 blockade, which might be beneficial in the treatment of chronic inflammatory diseases, such as multiple sclerosis, systemic lupus erythematosus, spontaneous autoimmune diabetes and atherosclerosis, as well as providing a mechanism for maintaining peripheral tolerance following allograft transplantation. [11][12][13] In contrast to CD40, CD40L is primarily expressed by activated CD4 þ T lymphocytes, but it is also present in mast cells, basophils, and platelets. 4 High levels of CD40L expression on a per cell basis are critical for receptor clustering and consequently CD40 signaling.…”

mentioning

confidence: 99%

Immune properties of recombinant vaccinia virus encoding CD154 (CD40L) are determined by expression of virally encoded CD40L and the presence of CD40L protein in viral particles

Bereta

Park

et al. 2004

Cancer Gene Ther

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Expression of costimulatory molecules by recombinant poxviruses is a promising strategy for enhancing therapeutic vaccines. CD40-CD40L interactions are critical for conditioning dendritic cells (DC) and priming T-and B-cell immunity. We constructed a vaccinia virus expressing murine CD40L (rV-CD40L) and studied its immunomodulatory properties in vitro. Direct DC infection with control vaccinia or psoralen/UV-inactivated rV-CD40L stimulated high levels of interleukin 12 (IL-12) release. However, replication-competent rV-CD40L did not stimulate IL-12 under similar conditions. We observed a high level of CD40L protein on purified viral particles and demonstrated that induction of IL-12 by nonreplicating rV-CD40L was blocked by anti-CD40 antibodies suggesting that functional CD40L on viral particles contributed to alterations in IL-12 synthesis.Since cross-presentation of tumor-associated antigens by DC is augmented by viral infection of tumor cells, we infected MC38 murine colon carcinoma cells with rV-CD40L. Infected cells stimulated IL-12 secretion by DC and proliferation of B cells and DX5 þ (NK/NKT) cells through direct CD40-CD40L interaction. A subpopulation of NKT cells expressing CD40 (NK1.1 þ , CD3 lo ) appeared to be a major effector population responding to MC38/rV-CD40L. These results highlight the complex immune regulatory effects of rV-CD40L defined by the cumulative effects of CD40L expression, presence of CD40L protein in viral particles, and the replication potential of the virus.

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CD40 Signaling and Plaque Instability

Cited by 506 publications

References 142 publications

CD40 Ligand–Dependent Tyrosine Nitration of Prostacyclin Synthase In Vivo

CD40 Ligand–Dependent Tyrosine Nitration of Prostacyclin Synthase In Vivo

The inflammatory receptor CD40 is expressed on human adipocytes: contribution to crosstalk between lymphocytes and adipocytes

Immune properties of recombinant vaccinia virus encoding CD154 (CD40L) are determined by expression of virally encoded CD40L and the presence of CD40L protein in viral particles

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