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PubMed2003

Increased susceptibility to airway responses in CD40-deficient mice.

The interaction between CD40 and its ligand (CD154) is crucial for IL-12 production and effective humoral immunity such as IgE production. Although the interaction seems to play a crucial role in asthmatic inflammation, previous studies investigating the role of the CD40 and CD154 interaction in experimental animal models of asthma are complicated due to multistep reactions in developing asthma. Here, in order to investigate the role of CD40 in the effector phase in the development of airway responses, we used CD40-deficient mice backcrossed with mice transgenic for an ovalbumin (OVA)-specific TCR (TCRtg). Using intranasal OVA administration followed by aerosol inhalation of OVA, greater airway hyperreactivity and eosinophilia in bronchoalveolar lavage fluid (BALF) were observed in CD40-deficient mice backcrossed with TCRtg mice (CD40-/-/ TCRtg mice), compared with control littermates (CD40+/+/ TCRtg mice). CD4+ helper T cell subset analysis of lung draining lymph nodes revealed that the Th1 component was significantly decreased in CD40-/-/ TCRtg mice. Airway hyperreactivity and airway eosinophilia significantly correlated with the predomination of Th2 cells. Cytokine measurements in BALF also showed decreased IL-12 and the predominance of Th2 cells in CD40-/-/ TCRtg mice. These results suggest that CD40 may play a protective role in developing asthma in the phase after establishing specific memory T cells through the regulation of the balance between Th1 and Th2 cells presumably via induction of IL-12.

Animals↗
PubMed2000

CD40 ligation alters the cell cycle of differentiating keratinocytes.

CD40 is expressed in normal human keratinocytes, especially in the basal cell layer. We have recently reported that CD40 ligation strongly inhibits keratinocyte proliferation and induces their differentiation. In this study, the CD40 pathway that prevents keratinocyte growth was investigated. We first reported that interferon-gamma treatment potentiated the CD40-mediated inhibition of keratinocyte proliferation. CD40-CD40 ligand interactions, in the presence or absence of interferon-gamma, neither enhanced spontaneous keratinocyte apoptosis, nor did it enhance apoptosis induced by various agents. More importantly, we showed that CD40 signaling altered the keratinocyte cell cycle, as demonstrated by a decreasing number of cells in the G1 and S phases and an accumulation in G2/M phase of the cell cycle. Furthermore, western blot analysis of cell cycle regulatory proteins, showed a decrease in cyclin A and E expression in CD40-activated keratinocytes. Collectively, these results indicate that CD40 ligation inhibits keratinocyte renewal by a mechanism independent of cell apoptosis and that modulation of the keratinocyte cell cycle is an additional outcome of CD40 signaling.

Apoptosis↗
PubMed1999

CD40 expression on graft infiltrates and parenchymal CD154 (CD40L) induction in human chronic renal allograft rejection.

BACKGROUND: CD40-CD154 (CD40L) costimulatory signaling plays a pivotal role in the effector mechanisms of transplant graft rejection. In animal models, CD40-CD154 blockade induces long-term graft acceptance concurrent with an absence of chronic rejection (CR) lesions. Given the critical importance of CD40-CD154 interactions in the development of chronic transplant allograft rejection, the relevance of in situ CD40 and CD154 expression was assessed in human chronic renal allograft rejection. METHODS: The expression of CD40, CD154, CD68, and T-cell receptor (TCR)alpha/beta was analyzed by immunohistochemistry. Serial cryostat sections of snap-frozen core renal allograft biopsies were obtained from 30 renal transplant patients. Biopsy specimens received diagnoses of CR (N = 23) according to the Banff classification and were compared with controls (N = 7) consisting of stable allografts and normal kidney tissue. RESULTS: Striking CD40 staining of graft cellular infiltrates (P = 0.016) was observed in renal allografts with CR compared with controls. The CD40+ cellular infiltrates in CR were predominantly TCR alpha/beta + T cells and some CD68+ macrophages. These findings were contrasted by the low-level CD40 expression detected in glomeruli and tubules of CR and controls. However, glomerular induction of CD154 was observed in CR allografts (P = 0.028) as compared with controls. CD154 immunoreactivity was demonstrated on glomerular endothelial, epithelial, and mesangial cells. Moderate CD154 expression was detected on tubular epithelial cells, and only weak CD154 immunoreactivity was observed on the infiltrates in isolated CR cases. CONCLUSION: In human chronic renal allograft rejection, CD40 is expressed on graft-infiltrating cells of the T cell and macrophage compartments. CD154 expression is induced on glomerular and tubular epithelial cells during CR, demonstrating another novel source of CD154 expression. The data substantiate the potential contributory role of an interaction between CD40+ graft-destructive effector T cells and macrophages with CD154+ renal allograft parenchymal cells in the development of chronic renal allograft rejection.

Antigens, CD↗
PubMed2003

Inhibition of phosphatidylinositol 3-kinase- and ERK MAPK-regulated protein synthesis reveals the pro-apoptotic properties of CD40 ligation in carcinoma cells.

CD40, a member of the tumor necrosis factor receptor superfamily, is frequently expressed in carcinomas where its stimulation results in induction of apoptosis when de novo protein synthesis is inhibited. The requirement of protein synthesis inhibition for efficient killing suggests that CD40 transduces potent survival signals capable of suppressing its pro-apoptotic effects. We have found that inhibition of CD40 signaling on the phosphatidylinositol 3-kinase (PI3K) and ERK MAPK but not on the p38 MAPK axis disrupts this balance and sensitizes carcinoma cells to CD40-mediated cell death. The CD40-mediated PI3K and ERK activities were found to converge on the regulation of protein synthesis in carcinoma cells via a pathway involving the activation of p90 ribosomal S6 kinase (p90Rsk) and p70S6 kinases, upstream of the translation elongation factor eEF2. In addition, CD40 ligation was found to mediate a PI3K- and mammalian target of rapamycin (mTOR)-dependent phosphorylation of 4E-BP1 and its subsequent dissociation from the mRNA cap-binding protein eIF4E as well as an ERK-dependent phosphorylation of eIF4E, thus promoting translation initiation. Concomitantly, the antiapoptotic protein cFLIP was found to be induced in CD40 ligand-stimulated carcinoma cells in a PI3K-, ERK-, and mammalian target of rapamycin (mTOR)-dependent manner and down-regulation of cFLIPS expression sensitized to CD40-mediated carcinoma cell death. These data underline the significance of the PI3K and ERK pathways in controlling the balance between CD40-mediated survival and death signals through the regulation of the protein synthesis machinery. Pharmacological agents that target this machinery or its upstream kinases could, therefore, be exploited for CD40-based tumor therapy.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Tumor necrosis factor receptor-associated factor (TRAF) 1 regulates CD40-induced TRAF2-mediated NF-kappaB activation.

To investigate CD40 signaling complex formation in living cells, we used green fluorescent protein (GFP)-tagged CD40 signaling intermediates and confocal life imaging. The majority of cytoplasmic TRAF2-GFP and, to a lesser extent, TRAF3-GFP, but not TRAF1-GFP or TRAF4-GFP, translocated into CD40 signaling complexes within a few minutes after CD40 triggering with the CD40 ligand. The inhibitor of apoptosis proteins cIAP1 and cIAP2 were also recruited by TRAF2 to sites of CD40 signaling. An excess of TRAF2 allowed recruitment of TRAF1-GFP to sites of CD40 signaling, whereas an excess of TRAF1 abrogated the interaction of TRAF2 and CD40. Overexpression of TRAF1, however, had no effect on the interaction of TRADD and TRAF2, known to be important for tumor necrosis factor receptor 1 (TNF-R1)-mediated NF-kappaB activation. Accordingly, TRAF1 inhibited CD40-dependent but not TNF-R1-dependent NF-kappaB activation. Moreover, down-regulation of TRAF1 with small interfering RNAs enhanced CD40/CD40 ligand-induced NF-kappaB activation but showed no effect on TNF signaling. Because of the trimeric organization of TRAF proteins, we propose that the stoichiometry of TRAF1-TRAF2 heteromeric complexes ((TRAF2)2-TRAF1 versus TRAF2-(TRAF1)2) determines their capability to mediate CD40 signaling but has no major effect on TNF signaling.

CD40 Antigens↗
PubMed2001

CD40-mediated signaling in monocytic cells: up-regulation of tumor necrosis factor receptor-associated factor mRNAs and activation of mitogen-activated protein kinase signaling pathways.

The biochemical pathways involved in CD40 signaling have been extensively studied in B cells and B cell lines, and appear to be primarily initiated by recruitment of the tumor necrosis factor (TNF) receptor-associated factor (TRAF) signaling proteins to the CD40 cytoplasmic domain. Signaling pathways activated through CD40 in monocytes/macrophages have not been characterized as well as in B cells. Using human monocytes and the human monocytic cell line THP1, we examined signal transduction events induced by CD40 engagement with its ligand, CD154. In human monocytes, all TRAF mRNAs were expressed constitutively and CD40 ligation resulted in a strong up-regulation of TRAF1 mRNA. In THP1 cells, CD40 ligation induced expression of TRAF1 and TRAF5 mRNAs. Engagement of CD40 in both monocytes and THP1 cells led to the rapid and transient activation of the extracellular signal-regulated kinases (ERK) 1 and 2, and to low levels of JNK activation. No CD40-dependent activation of p38 mitogen-activated protein kinase (MAPK) was found. In CD154-stimulated monocytes and THP1 cells the upstream ERK1/2 activator, MAPK kinase (MEK) 1/2, and downstream substrate, c-Myc, were activated. By blocking activation of ERK1/2 with a MEK-specific inhibitor, PD98059, CD40-dependent secretion of the pro-inflammatory cytokines, TNF-alpha, IL-6 and IL-8, was demonstrated to be linked to the ERK1/2 pathway. The ERK1/2 pathway did not appear to be involved in up-regulating TRAF1 and TRAF5 mRNAs in THP1 cells. Collectively, these results suggest distinct differences between B cells and monocytic cells in CD40-dependent activation of MAPK pathways.

B-Lymphocytes↗
PubMed2004

Induction of endothelin-1 production in endothelial cells via co-operative action between CD40 and lectin-like oxidized LDL receptor (LOX-1).

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), originally identified as the major receptor for oxidized low-density lipoprotein in endothelial cells, mediates the interaction between activated platelets and endothelial cells. Stimulation of LOX-1 causes various functional changes in endothelial cells relevant to 'endothelial dysfunction'. This study investigated the cellular responses to platelet binding via LOX-1, comparing it with CD40, which also mediates platelet-binding in endothelial cells. Activated platelets, which bind both LOX-1 and CD40, induced endothelin-1 production via co-operation of LOX-1 and CD40. Stimulation of LOX-1 by oxidized low-density lipoprotein induced the expression of CD40 as well as LOX-1 itself, and stimulation of CD40 by CD40L induced the expression of LOX-1 as well as CD40. Activated platelets induced both LOX-1 and CD40 expression via these two systems in endothelial cells. Application of superoxide dismutase suppressed LOX-1-mediated, but not CD40-mediated, induction of endothelin-1. LOX-1 and CD40 synergistically, but through a distinct pathway, work to induce endothelin-1 expression in endothelial cells. This co-operative action between LOX-1 and CD40 might play a key role in the induction of endothelial dysfunction.

Animals↗
PubMed2000

CD40 induces apoptosis in carcinoma cells through activation of cytotoxic ligands of the tumor necrosis factor superfamily.

CD40, a tumor necrosis factor (TNF) receptor (TNFR) family member, conveys signals regulating diverse cellular responses, ranging from proliferation and differentiation to growth suppression and cell death. The ability of CD40 to mediate apoptosis in carcinoma cells is intriguing given the fact that the CD40 cytoplasmic C terminus lacks a death domain homology with the cytotoxic members of the TNFR superfamily, such as Fas, TNFR1, and TNF-related apoptosis-inducing ligand (TRAIL) receptors. In this study, we have probed the mechanism by which CD40 transduces death signals. Using a trimeric recombinant soluble CD40 ligand to activate CD40, we have found that this phenomenon critically depends on the membrane proximal domain (amino acids 216 to 239) but not the TNFR-associated factor-interacting PXQXT motif in the CD40 cytoplasmic tail. CD40-mediated cytotoxicity is blocked by caspase inhibitors, such as zVAD-fmk and crmA, and involves activation of caspase 8 and caspase 3. Interestingly, CD40 ligation was found to induce functional Fas ligand, TRAIL (Apo-2L) and TNF in apoptosis-susceptible carcinoma cells and to up-regulate expression of Fas. These findings identify a novel proapoptotic mechanism which is induced by CD40 in carcinoma cells and depends on the endogenous production of cytotoxic cytokines and autocrine or paracrine induction of cell death.

Amino Acid Motifs↗
PubMed2002

Activation-induced cell death of aggressive histology lymphomas by CD40 stimulation: induction of bax.

CD40 is present on both normal and neoplastic B-lineage cells. CD40 stimulation of normal B cells has been shown to promote normal growth and differentiation, whereas aggressive histology B lymphomas are growth inhibited. The inhibition of neoplastic B-cell growth is believed to occur via activation-induced cell death in which stimuli that typically promote the growth of normal cells prevent the growth of their neoplastic counterparts. We show here that CD40 stimulation using either a soluble recombinant human CD40 ligand (srhCD40L) or anti-CD40 monoclonal antibody resulted in apoptosis of human Burkitt lymphoma cell lines. Additional studies examining the mechanism of CD40-mediated death revealed an increase in bax messenger RNA with a subsequent increase in Bax protein in the mitochondria of the treated cells. In vitro exposure of the cells to bax antisense oligonucleotides resulted in a significant decline in Bax protein levels and partial protection from CD40-mediated death, indicating that induction of Bax was at least one mechanism underlying this inhibitory effect of CD40 stimulation on lymphomas. When immunodeficient mice bearing Burkitt lymphoma were treated with srhCD40L, significant increases in survival were observed indicating a direct antitumor effect as a result of CD40 stimulation in vivo. Overall, these results demonstrate that CD40 ligation of aggressive histology B-lymphoma cells results in inhibition both in vitro and in vivo and thus may be of potential clinical use in their treatment.

Animals↗
PubMed1996

Functions of CD40 and its ligand, gp39 (CD40L).

Initially, a role for the interaction between CD40, expressed on B cells, and gp39 (CD40L), expressed on activated T cells, has been defined in humoral immunity. CD40-CD40L interaction is an essential signal for B cell proliferation, expression of activation markers, immunoglobulin production, and isotype switching. CD40-CD40L interaction is also required for formation of B memory cells and germinal centers, and signaling through CD40 prevents apoptosis of germinal center B cells. Defective expression of CD40L in humans leads to an inability to produce isotypes other than IgM (hyper IgM syndrome), and to an absence of germinal centers. More recent evidence indicates an expansion of the role of the CD40-CD40L axis in cellular interactions beyond antibody formation. Induced expression of CD40 on monocytes can lead to CD40L-activated monocyte effector mechanisms. In addition, CD40-CD40L interactions are crucially involved in development of autoimmune disease in a number of animal models. CD40-CD40L interactions also impact on growth regulation of certain carcinomas. Manipulation of CD40L has also been used to develop novel strategies for long-term antigen-specific tolerization of peripheral T cells. Finally, the CD40-CD40L axis is involved in thymic selection. Following is a comprehensive overview of CD40L-CD40 interactions in physiological and pathogenic cellular responses and a discussion of the therapeutic ramifications of these interactions.

Animals↗
PubMed2001

CD40 activation of carcinoma cells increases expression of adhesion and major histocompatibility molecules but fails to induce either CD80/CD86 expression or T cell alloreactivity.

A major obstacle for the development of cancer immunotherapy is the poor capacity of most tumor cells to present antigen. It has previously been shown that ligation of CD40 on the surface of malignant B cells results in the induction of efficient antigen presentation primarily because of upregulated expression of MHC, costimulatory, and adhesion molecules. Ongoing clinical trials are testing the impact of CD40 ligation as immunotherapy for B cell malignancies. Because CD40 is also widely expressed in carcinomas, we studied whether CD40 activation of these cells using soluble recombinant trimeric human CD40 ligand (srhCD40L) can also induce T cell responses. Here, we show that carcinoma cells upregulate expression of CD54 and MHC molecules following in vitro exposure to srhCD40L but do not upregulate CD80 or CD86. CD40-activated carcinoma cells failed to trigger mixed lymphocyte reactions, in sharp contrast to CD40-activated lymphoma cells for which CD40 activation, as expected, resulted in increased expression of MHC, adhesion, and costimulatory molecules, and generated brisk allogeneic lymphocyte reactions. Retroviral-mediated expression of CD80 in carcinoma cells, with or without CD40 activation, triggered mixed lymphocyte reactions, provided cells were treated with IFN-gamma. Thus, the cell surface phenotype induced on carcinoma cells following CD40 activation is not fully capable of inducing T cell proliferation; however, these results support ongoing efforts to exploit costimulation in clinical efforts aimed at increasing carcinoma immunogenicity.

Antigen Presentation↗
PubMed2005

Simultaneous targeting of CD3 on T cells and CD40 on B or dendritic cells augments the antitumor reactivity of tumor-primed lymph node cells.

To date, molecular targets chosen for Ab activation to generate antitumor effector cells have been confined on T cells, such as TCR/CD3, CD28, CD137 (4-1BB), CD134 (OX40), and inducible costimulator. In this report we investigated the immune function of murine tumor-draining lymph node (TDLN) cells after simultaneous Ab targeting of CD3 on T cells and CD40 on APCs. Anti-CD3 plus anti-CD40-activated TDLN cells secreted significantly higher amounts of IFN-gamma, but less IL-10, compared with anti-CD3-activated cells. In adoptive immunotherapy, ligation of CD3 and CD40 resulted in the generation of more potent effector cells in mediating tumor regression. Freshly harvested TDLN cells were composed of approximately 60% CD3+ T cells, 30-35% CD19+ B cells, 5% CD11c+ dendritic cells (DC), and few CD14+ or NK cells (each <3%). CD40 was distributed predominantly on B cells and DCs. Cell depletion indicated that simultaneous targeting was toward CD3 on T cells and CD40 on APCs, respectively. Elimination of APCs completely abrogated the augmented antitumor responses induced by anti-CD40. Either B cell or DC removal partially, but significantly, reduced the therapeutic efficacy conferred by CD40 engagement. Furthermore, the immunomodulation function of anti-CD40 was associated with its capability to increase IL-12 secretion while inhibiting IL-4 production. Our study establishes a role for CD40 expressed on B cells or DCs in the costimulation of TDLN cells. Eliciting antitumor activity via simultaneous targeting of CD3 on T cells and CD40 on APCs is relevant for the design of effective T cell-based cancer immunotherapy.

Animals↗
PubMed1996

CD40, but not lipopolysaccharide and anti-IgM stimulation of primary B lymphocytes, leads to a persistent nuclear accumulation of RelB.

In this study we analyzed the effect of CD40 stimulation on the activity and nuclear appearance of Rel/nuclear factor kappaB (NF-kappaB) factors in primary murine B lymphocytes. We show that triggering of CD40 signaling pathway(s) by CD40 ligands expressed on L cells led to strong activation of an NF-kappaB-controlled beta-globin reporter gene in primary B lymphocytes from transgenic mice. Analyses of nuclear translocation of individual members of Rel proteins after CD40 induction of primary B cells showed a strong and long-lasting accumulation of RelB and, less pronounced, of c-Rel. LPS stimulation did not give rise to a persistent nuclear accumulation of RelB and c-Rel, whereas nuclear c-Rel, but not RelB, accumulated after B cell receptor stimulation. CD40 induced not only nuclear translocation but also de novo synthesis of RelB RNA and protein. S107 plasmacytoma cells, which express CD40 but are defective for the nuclear appearance of p50/p65-NF-kappaB, do not express RelB after CD40 stimulation. In S107 cells stably transfected with relB genes, stimulation of nuclear RelB translocation by CD40 was observed. These results indicate that stimulation of CD40 signaling pathways exerts a long-lasting stimulatory effect on both the transcription and nuclear translocation of RelB. Since LPS and anti-IgM were unable to activate RelB, CD40 appears to trigger a special program of gene expression involved in the proliferation and/or differentiation of B lymphocytes.

Animals↗
PubMed1993

Protein tyrosine phosphorylation is mandatory for CD40-mediated rescue of germinal center B cells from apoptosis.

Spontaneous apoptosis in germinal center (GC) B cells can be arrested either by engaging cell surface immunoglobulin (Ig) with immobilized ligand or, more effectively, by treatment with soluble monoclonal antibody (mAb) directed against CD40. The present study examines the intracellular signal transduction pathways through which rescue from spontaneous apoptosis is engendered in GC B cells following ligation of surface CD40. Cross-linking the surface CD40 of GC B cells with mAb consistently resulted in enhanced tyrosine phosphorylation on a number of distinct substrates: this process could be blocked, in a dose-dependent fashion, by pre-treating GC B cells with the selective protein tyrosine kinase(s) (PTK) inhibitor, herbimycin A. Moreover, the pattern of phosphorylation on tyrosine observed following treatment with anti-CD40 was remarkably similar to that triggered by polyvalent anti-Ig. By contrast, anti-CD40 failed to stimulate the increase in inositol 1,4,5-trisphosphate and cytosolic free calcium observed in both GC B cells and resting B lymphocytes following ligation of surface Ig. The involvement of the signaling pathways generated in the rescue of GC B cells from apoptosis was studied by using selective inhibitors of PTK and of extracellular and intracellular Ca2+. Pre-incubation with the PTK inhibitor herbimycin A (5 microM) abrogated anti-CD40-mediated rescue of GC B cells from apoptosis, while genistein (40 microM) and the tyrphostins AG490 (10 microM) and AG814 (25 microM) significantly inhibited this process. Consistent with these results, herbimycin A (5 microM) abolished the expression of the 26 kDa bcl-2 protooncogene product, which confers resistance to apoptosis, normally observed following culture with anti-CD40. The Ca2+ chelators BAPTA and EGTA did not significantly affect CD40-promoted rescue. Taken together, these results indicate that CD40 of GC B cells is coupled to functional PTK but not to the phosphatidylinositol signaling pathway and that tyrosine phosphorylation is mandatory for CD40-mediated rescue of GC B cells from apoptosis.

Antibodies, Monoclonal↗
PubMed1995

CD40-mediated lymphotoxin alpha expression in human B cells is tyrosine kinase dependent.

The cytokine lymphotoxin (LT)alpha is known to play a role in B cell activation. As the engagement of the B cell antigen CD40 is known to lead to B cell proliferation and differentiation, we studied LT alpha expression in human B cells after CD40 ligation. We demonstrate that anti-CD40 monoclonal antibody (mAb) induces strong LT alpha mRNA and surface-expression in human tonsil B cells. Induction of LT alpha mRNA and surface expression by CD40 ligation is inhibited by the protein tyrosine kinase (PTK) inhibitors herbimycin and genistein in a dose-dependent manner. The protein kinase C (PKC)-specific inhibitors sphingosine and bis-indolylmaleimide caused negligible inhibition of anti-CD40-induced LT alpha mRNA and surface expression. No inhibition is observed with the protein kinase (PKA) inhibitors H89 and HA1004. Cross-linking of the transmembrane phosphatase CD45 to CD40 by using goat-anti-mouse F(ab')2 fragments strongly inhibits CD40-mediated LT alpha expression in human B cells, confirming the role of PTK activation in CD40-mediated induction of LT alpha expression. Inhibitors of the serine/threonine protein phosphatases PP1 and PP2A, okadaic acid and calyculin induce LT alpha mRNA expression. In contrast, cyclosporin A, an inhibitor of the serine/threonine phosphatase calcineurin has no effect on anti-CD40-induced LT alpha expression. These results suggest that induction of LT alpha expression in B cells following engagement of CD40 involves activation of protein tyrosine kinases.

Antibodies, Monoclonal↗
PubMed1996

CD40 is functionally expressed on human keratinocytes.

The CD40/gp39 pathway is known to be an important feature of B/T cell collaboration leading to T cell-dependent activation, proliferation or differentiation of B cells. Additionally, CD40 is involved in the regulation of B cell survival and apoptosis. Recently, CD40 has been shown to be expressed functionally on non-hematopoietic cells, i.e. endothelial cells. Here, we demonstrate that human keratinocytes (KC) cultured in vitro express CD40 constitutively. The surface expression of CD40 is markedly up-regulated following stimulation with interferon (IFN)-gamma, but not with tumor necrosis factor-alpha or interleukin (IL)-1 beta. This process is regulated at the CD40 mRNA level as demonstrated by Northern blot analysis. Furthermore, ligation of CD40 via soluble gp39, the CD40 ligand, enhances intercellular adhesion molecule (ICAM)-1 and Bcl-x up-regulation on IFN-gamma-stimulated KC, but not lymphocyte function-associated antigen (LFA)-3, B7-2, HLA-DR, or Fas expression. The release of IL-8 is also induced following CD40 ligation on KC. In psoriasis, a T cell-mediated inflammatory skin disease, KC have a markedly enhanced expression of CD40. This expression co-localizes with the expression of ICAM-1, Bcl-x, and an influx of CD3+ T cells. These findings suggest a functional role of CD40 on KC in inflammatory skin disorders such as psoriasis and could make a therapeutic intervention by disrupting the CD40/gp39 pathway an approach to consider in these inflammatory skin diseases.

Adult↗
PubMed2006

Rapid CD40-mediated rescue from CD95-induced apoptosis requires TNFR-associated factor-6 and PI3K.

The activation molecule CD40 and the death receptor CD95/Fas play important roles in regulating B cells so that effective antimicrobial immunity occurs without autoimmunity. CD40 signaling increases CD95 expression, sensitizing cells to apoptosis, but sustained CD40 signals rescue B cells from CD95 killing. Here we describe a mechanism of early CD40-mediated rescue from CD95-induced apoptosis in B cells. Maximal rescue was achieved when CD40 signals were given within 1-2 h of initiating CD95 apoptosis. CD40 signaling did not block association of Fas-associated death domain-containing protein with CD95, but decreased CD95-induced activation of caspases 3 and 8. Rapid CD40 rescue did not require NF-kappaB activation and was independent of de novo protein synthesis, but was dependent upon active PI3 K. Signaling via a CD40 mutant that does not bind TNFR-associated factor (TRAF)1, TRAF2, and TRAF3 rescued B cells from CD95-induced apoptosis. TRAF1/2/3-independent rescue was confirmed in B cell lines made deficient in these TRAF molecules by gene targeting. In contrast, CD40 rescue was completely abrogated in TRAF6-deficient B cells, which showed reduced activation of Akt in response to CD40 engagement. These results reveal a new rapid mechanism to balance B cell activation and apoptosis.

Animals↗
PubMed2005

Prognostic significance of CD40 expression in malignant lymphoma developing in rheumatoid arthritis.

PURPOSE: CD40, a member of tumor necrosis factor receptor superfamily, is expressed in synovial fluid B cells in rheumatoid arthritis (RA) and is postulated to contribute to RA progression. In this study, prognostic significance of CD40 expression was analyzed in B cell lymphoproliferative disorders (LPD) developing in RA. METHOD: CD40 expression was immunohistochemically examined in 35 cases of B-cell LPD developing in RA and in 32 of sporadic B-cell LPD as control. CD40 expression at mRNA level evaluated by quantitative reverse transcription-PCR and at protein level evaluated by immunohistochemistry correlated. RESULTS: Frequency of diffuse large B-cell lymphoma (DLBCL) in RA- and sporadic-LPD was 71.4 and 59.3%, respectively. CD40 positive rate in RA-LPD (62.9%) was significantly higher than that in sporadic LPD (37.5%) (P = 0.015). Interval between onset of RA and LPD development was shorter in CD40 positive cases than in negative cases (median 120 and 204 months, respectively) (P < 0.07). Five-year survival rate in CD40 positive DLBCL cases (75%) was significantly better than that in negative cases (25%) (P < 0.05). CONCLUSION: RA-LPD is characterized by the higher frequency of CD40 expression compared to sporadic LPD and CD40 positive cases which showed more favorable prognosis than those without CD40 expression.

Aged↗