The CD40/CD40L costimulatory pathway in inflammatory bowel disease

Danese, Silvio; Sans, Miquel; Fiocchi, Claudio

doi:10.1136/gut.2003.026278

Cited by 142 publications

(131 citation statements)

References 51 publications

Supporting

Mentioning

126

Contrasting

Unclassified

Order By: Relevance

“…Activation of the CD40 pathway in nonimmune cells leads to production of proinflammatory cytokines, chemokines and matrix metalloproteinases, and modulates apoptosis [32]. In agreement with this, addition of purified rCD40L to human adipocytes increased proinflammatory adipocytokine production.…”

Section: Discussionsupporting

confidence: 62%

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

et al. 2009

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 62%

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

et al. 2009

View full text Add to dashboard Cite

show abstract

“…It became evident that CD40L is not only expressed by activated T cells but also by other cell types following activation, especially in chronic inflammatory diseases and autoimmunity, and that it plays a broader role than initially thought. Indeed, the expression of CD40L by immune cells is augmented and prolonged in many disease conditions, including systemic lupus erythematosus (38), rheumatoid arthritis (39,40), inflammatory bowel disease (37), and cardiovascular disease (41), and is induced in non-immune cells such as fibroblasts (42) and endothelial cells (43). CD40L is also released as a soluble, trimeric, biologically functional molecule, and an increased level of circulating sCD40L is also a feature of many chronic inflammatory and autoimmune conditions (41, 44 -46).…”

Section: Discussionmentioning

confidence: 99%

CD40 Ligand Binds to α5β1 Integrin and Triggers Cell Signaling

Léveillé

Bouillon

Wen

et al. 2007

Journal of Biological Chemistry

110

View full text Add to dashboard Cite

It was originally thought that the critical role of the CD40 ligand (CD40L) in normal and inflammatory immune responses was mainly mediated through its interaction with the classic receptor, CD40. However, data from CD40L ؊/؊ and CD40؊/؊ mice suggest that the CD40L-induced inflammatory immune response involves at least one other receptor. This hypothesis is supported by the fact that CD40L stabilizes arterial thrombi through an ␣IIb␤3-dependent mechanism. Here we provide evidence that soluble CD40L (sCD40L) binds to cells of the undifferentiated human monocytic U937 cell line in a CD40-and ␣IIb␤3-independent manner. Binding of sCD40L to U937 cells was inhibited by anti-CD40L monoclonal antibody 5C8, anti-␣5␤1 monoclonal antibody P1D6, and soluble ␣5␤1. The direct binding of sCD40L to purified ␣5␤1 was confirmed in a solid phase binding assay. Binding of sCD40L to ␣5␤1 was modulated by the form of ␣5␤1 expressed on the cell surface as the activation of ␣5␤1 by Mn 2؉ or dithiothreitol resulted in the loss of sCD40L binding. Moreover, sCD40L induced the translocation of ␣5␤1 to the Triton X-100-insoluble fraction of U937 cells, the rapid activation of the MAPK pathways ERK1/2, and interleukin-8 gene expression. The binding of sCD40L to CD40 on BJAB cells, an ␣5␤1-negative B cell line, and the resulting activation of ERK1/2 was not inhibited by soluble ␣5␤1, suggesting that sCD40L can bind concomitantly to both receptors. These results document the existence of novel CD40L-dependent pathways of physiological relevance for cells expressing multiple receptors (CD40, ␣5␤1, and ␣IIb␤3) for CD40L. (2). The expression of CD154 is inducible, and its expression on T cells is triggered primarily by T cell receptor signaling and is regulated by CD28-dependent and independent pathways (3) CD40L is stored in platelets and a subpopulation of T cells and rapidly translocates to the cell membrane following T cell and platelet activation (4, 5). A soluble form of biologically active CD40L trimer (sCD40L) is present in the supernatant of activated T cells (6) and platelets (7) and results from the proteolytic cleavage of the homotrimeric CD40L by a metalloproteinase (7).It was originally thought that CD40L had only one receptor, CD40, which is a type I transmembrane protein that is a member of the TNF receptor superfamily. CD40 is expressed on the surface of many immune and non-immune cells, including B lymphocytes, monocytes/macrophages, and dendritic cells, as well as platelets, epithelial, and endothelial cells (8). Most biological functions of CD40L have been attributed to its direct interaction with CD40. However, studies using CD40L Ϫ/Ϫ and CD40 Ϫ/Ϫ mice have suggested that CD40L may also bind to one or more other receptors (9). In support of this hypothesis, it has been elegantly demonstrated that sCD40L interacts with ␣IIb␤3 (GPIIb/IIIa), an integrin expressed on platelets (10), triggering outside-in signaling and inducing platelet activation and spreading (11). CD40L Ϫ/Ϫ mice exhibit increased bleeding time (12) and reduce...

show abstract

“…In active IBD tissue, CD40 is up-regulated in several cell types including microvascular endothelial cells, whereas CD40L is overexpressed by lamina propria T cells and platelets, and its soluble form (sCD40L) is increased in the circulation of IBD patients (7, 8, 10 -12). These observations strongly indicate that the CD40/CD40L pathway plays a key pathogenic role in intestinal inflammation (13). The up-regulation of CD40 in the microcirculation of IBD-involved mucosa is of particular interest because the CD40 pathway is intimately involved in vascular inflammation.…”

mentioning

confidence: 89%

TNF-α Blockade Down-Regulates the CD40/CD40L Pathway in the Mucosal Microcirculation: A Novel Anti-Inflammatory Mechanism of Infliximab in Crohn’s Disease

Danese¹,

Sans

Scaldaferri³

et al. 2006

The Journal of Immunology

154

101

View full text Add to dashboard Cite

The CD40/CD40 ligand (CD40L) pathway is involved in Crohn’s disease (CD) pathogenesis. In the patients’ circulation, soluble CD40L (sCD40L) levels are elevated and surface CD40L is increased in platelets and T cells, whereas in the intestine CD40 is overexpressed in the microvasculature and CD40L in platelets and T cells. The therapeutic effects of infliximab in CD are attributed to its systemic anti-TNF-α action, but because TNF-α modulates both CD40 and CD40L, we investigated whether infliximab affects the CD40/CD40L pathway in the intestine. Eighteen CD patients were evaluated before and after infliximab therapy. Plasma sCD40L was measured by ELISA and platelet and peripheral blood T cell (PBT) CD40L expression by flow cytometry. Microvascular CD40 and VCAM-1 expression were assessed in mucosal biopsies by immunohistochemistry and by flow cytometry in human intestinal microvascular endothelial cells (HIMEC). Cell cultures were performed in the presence and absence of infliximab. Infliximab treatment significantly reduced plasma sCD40L levels and eliminated CD40 and VCAM-1 from mucosal microvessels. In vitro infliximab prevented TNF-α-induced CD40 and VCAM-1 expression by HIMEC, and reduced PBT, but not platelet, surface CD40L expression and sCD40L release. In addition, infliximab decreased T cell-induced VCAM-1 expression in HIMEC by down-regulating CD40L in T cells and promoting T cells apoptosis. These findings point to a novel mechanism of action of infliximab, i.e., the disruption of CD40/CD40L-dependent cognate interactions between intestinal microvessels and T cells. Thus, in addition to neutralizing TNF-α and inducing T cell death, the therapeutic effects of infliximab in CD appear to be also mediated by inhibition of vascular inflammation in the gut.

show abstract

The CD40/CD40L costimulatory pathway in inflammatory bowel disease

Cited by 142 publications

References 51 publications

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

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

CD40 Ligand Binds to α5β1 Integrin and Triggers Cell Signaling

TNF-α Blockade Down-Regulates the CD40/CD40L Pathway in the Mucosal Microcirculation: A Novel Anti-Inflammatory Mechanism of Infliximab in Crohn’s Disease

Contact Info

Product

Resources

About