CD40 and Its Ligand

Clark, Lisa B.; Foy, Teresa M.; Noelle, Randolph J.

doi:10.1016/s0065-2776(08)60854-8

Cited by 144 publications

(97 citation statements)

References 144 publications

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“…Similarly, TRAF3 was detected in immuno- precipitates of the AntpCD40/3-treated monocytic cell line, THP1. 3 Although TRAFs 2 and 6 were not detected by immunoblot analysis (data not shown), a reproducible increase in expression of the CD40-inducible intercellular adhesion molecule 1 protein was detected in AntpCD40/3-treated DND39 B cells. 3,4 Together these results imply that soluble trimeric AntpCD40/3 was introduced into B cells and formed functional signaling complexes.…”

Section: Soluble Trimeric Cd40c Is Complexed With Endogenous Trafs Anmentioning

confidence: 86%

“…Signals generated through CD40 in B cells are antiapoptotic and are required for T cell-dependent B cell activation and proliferation, isotype switching, up-regulation of costimulatory receptors, germinal center formation, and memory generation (1,3,4). Signal transduction through CD40 is initiated by binding trimeric CD40 ligand on the surface of activated T cells (1,5).…”

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confidence: 99%

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Molecular Characterization of CD40 Signaling Intermediates

Werneburg

Zoog

Dang

et al. 2001

Journal of Biological Chemistry

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The tumor necrosis factor (TNF) 1 receptor superfamily member CD40 is expressed primarily by professional antigen-presenting cells and plays a critical role in costimulation and antigen-presenting cell activation in T cell-dependent immune responses (1, 2). Signals generated through CD40 in B cells are antiapoptotic and are required for T cell-dependent B cell activation and proliferation, isotype switching, up-regulation of costimulatory receptors, germinal center formation, and memory generation (1, 3, 4). Signal transduction through CD40 is initiated by binding trimeric CD40 ligand on the surface of activated T cells (1, 5). Signaling pathways highly activated by CD40 engagement in B cells include NF-B and the mitogenactivated protein kinases p38 and c-Jun N-terminal kinase (6 -10).Activation of CD40-dependent signaling pathways is thought to be mediated primarily by recruitment of several TRAF protein family members to the multimerized CD40 cytoplasmic domain (for review, see Ref. 11). The 62-amino acid human CD40 cytoplasmic domain (CD40c) contains two linear TRAF binding sites, a membrane proximal site that binds TRAF6 and a membrane distal site that directly binds TRAF1, TRAF2, and TRAF3 (12-15). The conserved C-terminal half of the TRAF proteins, designated the TRAF domain, mediates interactions with multimerized receptor cytoplasmic domains (11,16,17).Crystal structures of the CD40 ligand trimer (5) and of the LT␣⅐TNFR1 and TRAIL⅐DR5 receptor complexes (18, 19) suggest that CD40 forms at least a trimeric complex upon binding its ligand. Recent x-ray crystallographic structures of TRAF2⅐CD40 and TRAF3⅐CD40 peptide complexes also demonstrate that the TRAF domains of TRAF2 and TRAF3 form trimers where the geometrical spacing of the CD40c peptides closely matches that of the extracellularly ligated CD40 receptor (20 -22). Biochemical experiments suggest that the requirement for CD40c trimerization in the recruitment of TRAF proteins is solely avidity-driven. As an alternative to dimerization, receptor trimerization may regulate initiation of CD40 signaling by providing a higher degree of discrimination between liganded and unliganded receptors (22)(23)(24). Differential TRAF recruitment and distinct cellular signaling outcomes depend on the extent of higher order CD40 multimerization (23,25,26). However, minimum multimerization requirements for CD40c to initiate signaling have not been defined in cells.

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Section: Soluble Trimeric Cd40c Is Complexed With Endogenous Trafs Anmentioning

confidence: 86%

mentioning

confidence: 99%

Molecular Characterization of CD40 Signaling Intermediates

Werneburg

Zoog

Dang

et al. 2001

Journal of Biological Chemistry

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“…Apoptosis-dependent and -independent growth inhibition has been suggested to occur in several tumors. 9 -11 The proapoptotic effect is supported by the molecular similarity of the intracellular domain of CD40 with the death domains of the p55 TNF receptor and Fas 27 and activation of cytotoxic ligands of the TNF superfamily. 28 However, CD40 signaling has been reported to prevent apoptosis in lymphocytes and in some tumors, such as bladder carcinomas.…”

Section: Discussionmentioning

confidence: 99%

Expression of CD154 on renal cell carcinomas and effect on cell proliferation, motility and platelet‐activating factor synthesis

Bussolati

Russo

Deambrosis

et al. 2002

Intl Journal of Cancer

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CD40 activation by CD154 may trigger diverse cellular responses, ranging from proliferation and differentiation to growth suppression and cell death, in normal and malignant cells. However, the pathophysiologic role of CD154 expressed by tumor cells remains unclear. We have investigated the expression of the CD40-CD154 system in 24 primary cultures derived from renal cell carcinomas, its correlation with tumor stage and its potential functional significance. We found coexpression of CD40 and CD154 in most of the renal carcinoma cell lines. CD154, but not CD40 expression, significantly correlated with tumor stage. Moreover, renal carcinoma cell lines also released the soluble form of CD154 into the supernatant. CD40 engagement by CD154 did not affect apoptosis or survival. On the contrary, CD154 stimulated cell proliferation, motility and production of PAF, a phospholipid mediator of inflammation with angiogenic properties. Key words: CD154; platelet-activating factor; renal carcinoma; CD40; angiogenesis CD154, the ligand of CD40, is a type II integral membrane protein, related to TNF and FasL. 1 Its receptor, CD40, is a 50 kDa transmembrane glycoprotein of the TNF superfamily, which is expressed in a multitude of different cell types, including B cells, monocytes, dendritic cells, endothelial cells, fibroblasts and renal epithelial cells. 2,3 CD40 was originally identified in a bladder carcinoma cell line, 4 and it is also expressed in a number of carcinomas, such as ovarian, nasopharyngeal, bladder, lung, colon and breast carcinomas, whereas normal nonproliferating tissues are CD40-negative. 5 CD40 engagement by CD154 conveys signals regulating diverse cellular responses, ranging from proliferation and differentiation to growth suppression and apoptosis. 6,7 The CD40 cytoplasmic C terminus lacks intrinsic kinase activity and adapter proteins of the TRAF family appear to mediate the activation of CD40-signaling cascades. 8 Despite the large interest, the functional role of CD40 in cancer development remains undetermined. CD40 appears to possess an opposite effect on tumor cell survival and apoptosis. CD40-mediated signaling has been reported to induce apoptosis when expressed in certain transformed cells of mesenchymal origin 9 and in carcinomas of the breast and lung. 10,11 Conversely, Jakobson et al. 12 demonstrated that CD40 stimulation inhibits Fas-mediated apoptosis in human bladder carcinoma cells and we showed a similar protective effect of CD40 in Kaposi's sarcoma cells. 13 Moreover, immunohistochemic studies revealed that detection of CD40 in primary cutaneous malignant melanoma might have negative prognostic value, suggesting its role in tumor progression. 14 CD154 is coexpressed with CD40 in melanoma cells and some carcinomas. 10,11,14 However, the pathophysiologic role of CD40 -CD154 interaction within the tumor cell remains unclear.In the present study, we investigated expression of the CD40 -CD154 system in 24 primary cultures derived from renal clear cell carcinomas, its correlation with tumor st...

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“…[16][17][18]. With regard to the production of cytokines and chemokines in response to CD40 ligation, the importance of IKK and MAPKs has been demonstrated.…”

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confidence: 99%

Amplification of the synovial inflammatory response through activation of mitogen‐activated protein kinases and nuclear factor κB using ligation of CD40 on CD14+ synovial cells from patients with rheumatoid arthritis

Harigai¹,

Hara²,

Kawamoto³

et al. 2004

Arthritis & Rheumatism

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Objective. To determine the signal transduction pathways in CD14؉ synovial cells from patients with rheumatoid arthritis (RA) after CD40 ligation, and to examine their role in amplifying synovial inflammation in affected joints.Methods. Expression of messenger RNA was analyzed using quantitative reverse transcriptionpolymerase chain reaction. Cytokines and chemokines were measured using enzyme-linked immunosorbent assay. Activation of kinases was detected using Western blotting. Nuclear translocation of NF-B was examined using immunohistochemistry. CD14؉ synovial cells were enriched using magnetic cell sorting. Fibroblastlike synoviocytes (FLS) were obtained by passaging primary synovial cell culture.Results. Stimulation of CD14؉ synovial cells from RA patients by recombinant soluble CD154 (rsCD154) significantly induced expression of tumor necrosis factor ␣ (TNF␣),

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CD40 and Its Ligand

Cited by 144 publications

References 144 publications

Molecular Characterization of CD40 Signaling Intermediates

Molecular Characterization of CD40 Signaling Intermediates

Expression of CD154 on renal cell carcinomas and effect on cell proliferation, motility and platelet‐activating factor synthesis

Amplification of the synovial inflammatory response through activation of mitogen‐activated protein kinases and nuclear factor κB using ligation of CD40 on CD14+ synovial cells from patients with rheumatoid arthritis

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