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PubMed2004

Anti-CD40 ligand monoclonal antibody induces a permissive state, but not tolerance, for murine peripheral nerve allografts.

Anti-CD40 ligand monoclonal antibody prevents the interaction between CD40 and its T-cell-based ligand, thereby resulting in selective inhibition of T cell costimulation without pan-T-cell suppression. This antibody has found application in several animal models of solid organ transplantation. This study investigated use of anti-CD40 ligand antibody to promote acceptance of nerve allografts. In Experiment 1, 40 BALB/cj mice with tibial nerve transplants were administered anti-CD40 ligand antibody, a control antibody, or no treatment. In Experiment 2, 40 BALB/cj mice underwent the same regimen as in Experiment 1, but were later challenged with a second nerve allograft 3 weeks after discontinuation of treatment. Animals treated with anti-CD40 ligand antibody in Experiment 1 exhibited improved functional recovery and greater mean fiber count, fiber density, and percent nerve fiber than animals treated with control antibody or no antibody (P < 0.05). These permissive effects on nerve regeneration were associated with immune unresponsiveness on Elispot assay. The benefit of anti-CD40 ligand therapy did not persist after withdrawal of treatment (Experiment 2). Active blockade of the CD40 costimulatory pathway with murine anti-CD40 ligand antibody therefore induces a permissive state conducive to nerve regeneration across allografts but does not establish long-term tolerance.

Animals↗

PubMed2005

DNFB activates MAPKs and upregulates CD40 in skin-derived dendritic cells.

BACKGROUND: The intracellular mechanisms involved in the activation of DCs during sensitization in allergic contact dermatitis (ACD) are not known. OBJECTIVE: Here, we investigated the effect of a strong sensitizer, 2,4-dinitrofluorobenzene (DNFB) on the activity of MAPKs in a dendritic cell (DC) line generated from fetal mouse skin (FSDC), and the results were correlated with the expression of a costimulatory molecule upregulated upon DC maturation, CD40. METHODS: Phosphorylation of ERK1/2 (pERK1/2) and p38 MAPK (pp38 MAPK), and CD40 protein levels, were determined by Western blot. Cellular localization of pERK1/2 and pp38 MAPK were determined by immunocytochemistry using phospho-specific antibodies. RESULTS: Although with different kinetics, DNFB activated ERK1/2 and p38 MAPK, and induced the translocation of the phosphorylated forms of the kinases to the nucleus. In addition, DNFB upregulated significantly CD40 protein levels in FSDC. However, 2,4-dichloronitrobenzene (DCNB), an inactive analogue of DNFB, did not affect significantly the phosphorylation of MAPKs and CD40 protein levels. SB203580 and SB202190, inhibitors of the p38 MAPK activity, inhibited DNFB-induced CD40 upregulation, although this effect did not reach statistical significance. In contrast, PD 98059 and U0126, inhibitors of mitogen or extracellular signal-regulated kinase (MEK), had no effect on the CD40 upregulation induced by DNFB. CONCLUSIONS: Taken together, these results indicate that the strong sensitizer DNFB activates ERK1/2 and p38 MAPK signaling pathways, and upregulates CD40 protein levels. However, MAPKs do not play a major role in the induction of CD40, one of the phenotypic markers of DC maturation.

Active Transport, Cell Nucleus↗

PubMed2002

CD40-mediated tumor necrosis factor receptor-associated factor 3 signaling upregulates IL-4-induced germline Cepsilon transcription in a human B cell line.

Induction of germline C epsilon transcription in B cells by IL-4, which is a critical initiating step for IgE class switching, is enhanced by CD40 engagement. Although signaling by CD40 is initiated by the binding of tumor necrosis factor receptor-associated factor (TRAF) family members to its cytoplasmic domain, whether those TRAF family proteins mediate enhancement of germline Cepsilon transcription is not evident. We report here that CD40-induced TRAF3-dependent activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase 1 (MEK1) is involved in the upregulation of IL-4-driven germline C epsilon transcription in a human Burkitt's lymphoma B cell line, DG75. Among the six known TRAF proteins, TRAF2, 3, 5, and 6 associated with CD40 in an unstimulated state, and the levels of these four proteins were unaffected by anti-CD40 stimulation. Antisense oligodeoxynucleotide (ODN) for TRAF3 inhibited CD40-induced activation of MEK1-ERK pathway by decreasing expression of TRAF3 protein, but antisense ODNs for TRAF2, 5, and 6 were ineffective. Furthermore, CD40-mediated enhancement of IL-4-driven germline C epsilon transcription was inhibited by antisense ODN for TRAF3 and by a MEK1 inhibitor, PD98059. These results suggest that in DG75 cells, TRAF3-induced MEK1 activation may be involved in CD40-mediated upregulation of IL-4-driven germline C epsilon transcription.

Burkitt Lymphoma↗

PubMed1996

Increased inhibition of proliferation of human B cell lymphomas following ligation of CD40, and either CD19, CD20, CD95 or surface immunoglobulin.

Non-Hodgkin's (NHL) B cell lymphomas are growth-inhibited by ligation of their CD40 molecules. This inhibition is not absolute in that approximately 50% of the cells are not inhibited. We conducted studies to see if other signals that have been reported to inhibit B cell lymphoma growth could be used in combination with anti-CD40 signaling to completely inhibit growth. Ligation of surface immunoglobulin (Ig), CD19, CD20, CD37 or CD95 with soluble antibody did not affect growth of the panel of NHL cells examined. Ligation of CD20, CD19 or CD95 was inhibitory for some NHL cell lines if the primary antibody was crosslinked with a secondary antibody. Combining anti-CD40 with anti-CD19, anti-CD20, or anti-Ig resulted in increased inhibition past that produced by anti-CD40 alone. The additive effect of anti-CD40 and other antibodies to selected surface markers was not observed in all NHL cell lines. Crosslinking of CD95 was also growth inhibitory for the majority of the NHL, and when combined with anti-CD40 under conditions that afforded crosslinking of the two receptors, increased inhibition was seen in three of the NHL cell lines. We found that cAMP or sodium butyrate (NaB) were also effective at inhibiting growth of the NHL cells; this was a profound inhibition (approaching 100%) compared to the 50% inhibition seen with anti-CD40 treatment. The potential for anti-CD40 and either cAMP or NaB to be additive was tested and not found to be the case. The ability to inhibit proliferation of the NHL was very dynamic with some antibody combinations being either inhibitory for multiple cells, not having an effect at all, or in some cases being stimulatory. This suggests that the NHL may represent unique stages of B cells that might serve as a model system which could be developed to precisely categorize patient NHL.

Antibodies, Monoclonal↗

PubMed1999

Involvement of a rapamycin-sensitive pathway in CD40-mediated activation of murine B cells in vitro.

Activation of resting B cells requires an initial triggering of the B cell antigen receptor (BCR) and secondary stimuli through various cytokine receptors and B cell activation molecules including CD40. We found that activation of B cells through CD40 is selectively inhibited by an immunosuppressant drug, rapamycin. This effect of rapamycin on anti-CD40-mediated activation of B cells was observed using three different in vitro assays. Rapamycin suppressed the anti-CD40-induced proliferation of splenic B cells, suppressed differentiation to surface IgMhigh/IgDlow B cells, and inhibited an anti-CD40-mediated prevention of apoptosis induced by BCR cross-linkage of WEHI-231 cells. We next examined several known CD40 signal transduction pathways to identify the target of rapamycin in stimulated B cells. Rapamycin did not inhibit the activation of c-Jun N-terminal kinases (JNKs) induced by anti-CD40 stimulation nor the activation of immediate nuclear transcription factors of NF-kappaB. Therefore, rapamycin affects a novel element of the CD40 signal transduction pathway which influences the proliferation, differentiation, and prevention of apoptosis of B cells.

Androstadienes↗

PubMed2001

Adenovector-induced expression of human-CD40-ligand (hCD40L) by multiple myeloma cells. A model for immunotherapy.

OBJECTIVE: CD40L restores the antigen-presenting cell (APC) function of some B-cell tumors and induces professional APC maturation. We therefore evaluated the effects of transgenic CD40L expression on the behavior and immunogenicity of human multiple myeloma (MM) cells. MATERIALS AND METHODS: CD40L expression was induced in a CD40(+) (RPMI 8226) and a CD40(-) (U266B1) human myeloma cell line (HMCL) by adenoviral vector gene transfer. The viability and proliferative activity of control HMCL and HMCL/CD40L were determined by daily trypan blue staining and methyl-3H-thymidine incorporation. Mixed lymphocyte reaction (MLR) with allogeneic mononuclear cells (MNCs) and coculture of allogeneic dendritic cells (DCs) with HMCL expressing transgenic CD40L were used to evaluate the APC function of modified HMCL as well as the role of bystander DCs in inducing an anti-tumor immune response. RESULTS: CD40L expression significantly inhibited the growth of the CD40(+) HMCL and induced apoptosis. These effects were less evident for the CD40(-) HMCL. There was no upregulation of costimulatory molecules on either HMCL following CD40L expression. Both HMCL expressing transgenic CD40L induced maturation of bystander DCs and enhanced their ability to stimulate the proliferation of MNCs. DCs cultured with the poorly immunogenic RPMI 8226 expressing CD40L upregulated T-lymphocyte release of IFN-gamma and other Th1 cytokines (interleukin-2, tumor necrosis factor-alpha). CONCLUSIONS: Our data suggest that transgenic expression of CD40L exerts a dual effect favoring generation of an immune response to human MM. Where the tumor cells are CD40(+), the engagement of CD40 antigen by CD40L on tumor cells induces their apoptosis, allowing uptake of tumor-associated antigen by professional APC. Independently of tumor-cell expression of CD40, transgenic expression of CD40L on tumor cells allows them to stimulate CD40(+) APC, to increase their maturation and their capacity to stimulate cytotoxic T lymphocytes (CTL) that recognize the tumor-derived antigens the APC may have engulfed.

Adenoviridae↗

PubMed2000

CD40 ligation inhibits trichilemmoma cell proliferation and induces IL-6 production.

CD40 is a member of the tumor necrosis factor receptor superfamily expressed by B cells, monocytes, dendritic cells, epithelial cells, and hematopoietic progenitor cells. Recently, CD40 has been reported to also be expressed on human epidermal cells. We have elucidated the function of CD40 on epidermal tumor cells and have found that trichilemmoma (KTL-1) cells constitutively express CD40 and respond to CD40 ligation by anti-CD40 mAb (EA-5) with a significant decrease in proliferation. We were also able to demonstrate that KTL-1 cells respond to CD40 ligation by EA-5 with the up-regulation of interleukin-6 (IL-6) mRNA expression. Together, the results suggest that CD40 on KTL-1 cells may function to regulate their proliferation associated with the induction of IL-6 production.

CD40 Antigens↗

PubMed2001

CD40 co-stimulatory molecule expression by dendritic cells in primary atherosclerotic lesions in carotid arteries and in stenotic saphenous vein coronary artery grafts.

We have previously identified dendritic cells in the intima of human large arteries and stenotic vein coronary bypass grafts. The mechanisms by which these dendritic cells might regulate immune responses in atherosclerotic lesions and stenotic vein grafts are unknown. The aim of the present study was to investigate whether dendritic cells in carotid plaques and in stenotic aortocoronary vein grafts express an immunoregulatory molecule CD40. Segments of wall from eight carotid arteries and three stenotic aortocoronary saphenous vein grafts were obtained at operation. CD40+ cells were detected in all specimens of both occluded and stenotic grafts and carotid plaques. Although CD40+ cells of various cell types were intermingled in most areas within the plaques and stenotic grafts, there were sites where CD40+ cells were located in small groups. Consecutive sections demonstrated that a small population of CD40+ cells stained positively for S100. These CD40+/S100+ cells were clustered within the intima but were also found in the media and adventitia. This suggests that dendritic cells, which accumulate within vessels affected by atherosclerosis and graft disease, express CD40 co-stimulatory molecule. The expression of CD40 molecule on the dendritic cells may be important in regulating T cell responses within atherosclerotic plaques and stenotic vein grafts.

CD40 Antigens↗

PubMed2002

Unimpaired activation of c-Jun NH2-terminal kinase (JNK) 1 upon CD40 stimulation in B cells of patients with X-linked agammaglobulinemia.

X-linked agammaglobulinemia (XLA) is caused by mutations in the gene encoding the cytoplasmic Bruton's tyrosine kinase (Btk). Btk has been shown to play an essential role in the development of B1 (CD5+) and conventional circulating mature B cells (B2) in mouse and man. It has been shown in earlier studies that Btk is involved in both the BCR- and CD40-mediated signaling pathways. In this study, we analyzed the responsiveness of Epstein-Barr virus (EBV) transformed B cells from nine XLA patients to CD40 stimulation, particularly the CD40 induced activation of c-Jun N-terminal kinase (JNK). In eight XLA patients the JNK activation was unimpaired and in one case INK could not be activated by anti-CD40 stimulation. Btk protein expression was detectable by Western blotting in six cases, in one case Btk expression was drastically reduced, and in three cases no Btk expression could be observed. Btk kinase activity was found in three cases and it was reduced in one and not detectable in five cases. Furthermore, in one female patient with an agammaglobulinemia, Btk expression and function as well as JNK activation by CD40 stimulation was unimpaired. Our findings demonstrate that INK activation via the CD40 signaling pathway is intact in EBV-transformed B cells of most if not all XLA patients, independent of the mutation and its effect on Btk expression and kinase activity. We suggest that Btk is not necessary for the activation of INK upon CD40 stimulation, at least in the B cell subpopulation we had studied. We cannot exclude that these B cells belong to a "leaky" B-cell subpopulation in which the CD40 signaling pathway has become independent of Btk function.

Agammaglobulinaemia Tyrosine Kinase↗

PubMed2004

Reciprocal CD40 signals through p38MAPK and ERK-1/2 induce counteracting immune responses.

Macrophages play host to Leishmania major, a parasite that causes leishmaniasis in 500,000 people annually. Macrophage-expressed CD40, a costimulatory molecule, induces interleukin-12 (IL-12)-dependent and interferon-gamma (IFN-gamma)-dependent host-protective immune responses to Leishmania and other intracellular pathogens. Paradoxically, IL-10, another CD40-induced cytokine in macrophages, promotes Leishmania infection. How CD40 signaling regulates the secretion of these two counteractive cytokines remains unknown. Here we show that weak CD40 signals induce extracellular stress-related kinase-1/2 (ERK-1/2)-dependent IL-10 expression, whereas stronger signals induce p38 mitogen-activated protein kinase (p38MAPK)-dependent IL-12 production. p38MAPK and ERK-1/2 therefore have counter-regulatory actions. Leishmania skews CD40 signaling toward ERK-1/2, inducing IL-10, which inhibits activation of CD40-induced p38MAPK and expression of inducible nitric oxide synthase-2 (iNOS-2) and IL-12. ERK-1/2 inhibition or IL-10 neutralization restores CD40-induced p38MAPK activation and parasite killing in macrophages and the BALB/c mouse, a susceptible host. These data uncover a new immune evasion strategy, whereby Leishmania differentially modulates CD40-engaged, reciprocally functioning signaling modules, and provide a new conceptual framework for immune homeostasis.

Animals↗

PubMed1997

Role of the CD40 and CD95 (APO-1/Fas) antigens in the apoptosis of human B-cell malignancies.

Ligation of CD40 inhibits apoptosis and stimulates proliferation of normal B cells, whereas ligation of CD95 (APO-1/Fas) induces apoptosis of activated lymphocytes. Aberrant signalling through the CD40 and CD95 antigens could thus participate in the pathogenesis of lymphoid malignancies. The expression and function of CD40 and CD95 on neoplastic B cells from patients with acute lymphoblastic leukaemia (ALL), chronic lymphocytic leukaemia (CLL) and non-Hodgkin's lymphoma (NHL) were examined. CD40 was expressed by all 30 B-cell tumours, whereas CD95 was detected on neoplastic B cells in only one of 10 cases of ALL, two of 10 cases of CLL, and three of 10 cases of NHL. Incubation with an agonistic CD95 monoclonal antibody (MoAb) did not augment apoptosis in any of the unstimulated B-cell neoplasms. CD40 triggering did not consistently inhibit spontaneous apoptosis, but ultimately stimulated the growth of neoplastic B cells in most cases. Furthermore, CD40 activation led to up-regulation of the CD95 antigen in all 30 B-cell neoplasms. Ligation of CD95 on CD40-activated tumour cells augmented apoptosis in five of 10 ALL, three of 10 CLL, and nine of 10 NHL cases. The degree of apoptosis induced by CD95 triggering was greater for NHL cells than for ALL cells or CLL cells. Bcl-2 expression by ALL and NHL cells was substantially decreased after in vitro culture, whereas Bcl-2 expression by CLL cells was not significantly changed. However, there was no correlation between the level of Bcl-2 expression and sensitivity to CD95-mediated apoptosis. Thus, factors other than levels of CD95 and Bcl-2 determine susceptibility of malignant B cells to apoptosis after CD95 triggering. CD40-activated lymphoma cells appear to be very sensitive to CD95-mediated apoptosis, suggesting potential strategies for treatment of NHL. Elucidation of the mechanisms underlying resistance of ALL and CLL cells to CD95 triggering may facilitate the development of novel therapeutic approaches to these diseases as well.

Apoptosis↗

PubMed2001

CD40 expression and function on human dermal microvascular endothelial cells: role in cutaneous inflammation.

CD40 is a member of the tumour necrosis factor (TNF) cell surface receptor family. It plays an important role in T-cell dependent B-cell functions and in dendritic cell development. It has also been identified as a cell surface receptor on endothelial cells. In this manuscript, we report that human dermal microvascular endothelial cells (HDMEC) express cell surface CD40 and that the expression of CD40 is increased by the proinflammatory cytokines TNF-alpha and interferon (IFN)-gamma. Additionally, we demonstrate that engagement of HDMEC CD40 with its recombinant CD40 ligand augments the induction of E-selectin, but not of intercellular or vascular cell adhesion molecules on the surface of HDMEC. Furthermore, we show that IFN gamma stimulation of HDMEC results in increased binding of Jurkat leucocytes to HDMEC by a CD40--CD154 dependent pathway. This study thus provides evidence that CD40 expression in HDMEC is regulated by proinflammatory cytokines, and that CD40 functions as an important mediator of cutaneous inflammation.

CD40 Antigens↗

PubMed1999

Differential effects of cytokines and immunosuppressive drugs on CD40, B7-1, and B7-2 expression on purified epidermal Langerhans cells1.

Langerhans cells are MHC class II antigen-positive antigen-presenting cells in the epidermis. Recent studies have revealed that Langerhans cells express costimulatory molecules like B7-1 and B7-2 and the accessory molecule CD40. Although these molecules are important for the antigen-presenting function of Langerhans cells, little is known about the precise regulation of their expression on purified Langerhans cells. Using a panning technique, we purified epidermal Langerhans cells to around 95% purity. Freshly prepared Langerhans cells (fLC) expressed the mRNA for receptors for M-CSF (cfms), GM-CSF (GM-CSFR), and TNF-alpha (TNFRII). TNF-alpha markedly upregulated CD40 and B7-1 expression on Langerhans cells, but not B7-2 expression. GM-CSF moderately upregulated B7-1 and B7-2 expression, and slightly upregulated CD40 expression. M-CSF moderately upregulated B7-1 expression, but did not modulate CD40 or B7-2 expression. Dexamethasone (DEX) markedly inhibited CD40, B7-1, and B7-2 expression on Langerhans cells. Cyclosporin A (CsA) and FK506 slightly inhibited CD40 and B7-1 expression on Langerhans cells, but not B7-2. Furthermore, TNF-alpha restored the DEX-induced inhibition of CD40 expression on Langerhans cells, but not the inhibition of B7-1 or B7-2 expression. GM-CSF restored DEX-induced inhibition of CD40, B7-1, and B7-2 expression. M-CSF did not affect the DEX-induced inhibition of these molecule expressions. These data provide a better understanding of the role of selective cytokines and immunosupressive drugs in the modulation of the antigen-presenting capacity of Langerhans cells.

Animals↗

PubMed2002

Ketoconazole suppresses interleukin-4 plus anti-CD40-induced IgE class switching in surface IgE negative B cells from patients with atopic dermatitis.

We previously reported that antimycotic agent ketoconazole suppressed interleukin-4 production in T cells from patients with atopic dermatitis. We herein studied if ketoconazole may suppress B cell IgE class switching. Interleukin-4 plus anti-CD40-induced IgE secretion was enhanced in peripheral blood surface IgE- B cells from atopic dermatitis patients compared to those from normal donors, and the secretion was inhibited by ketoconazole. Ketoconazole suppressed interleukin-4 plus anti-CD40-induced germline and mature epsilon transcripts in surface IgE- B cells. Ketoconazole also inhibited interleukin-4 plus anti-CD40-induced activation of germline epsilon promoter in human Burkitt lymphoma Ramos cells. The regions -171/-155 bp containing CCAAT/enhancer-binding protein element and -155/-109 bp containing Stat6 and nuclear factor kappaB elements were required for the ketoconazole-induced inhibition of the germline epsilon promoter activity. Ketoconazole inhibited interleukin-4 plus anti-CD40-induced enhancer activities of CCAAT/enhancer-binding protein and nuclear factor kappaB, and those of composite elements of CCAAT/enhancer-binding protein/Stat6 or of Stat6/nuclear factor kappaB, but did not alter that of Stat6 in Ramos cells. cAMP analog reversed the inhibitory effects of ketoconazole on interleukin-4 plus anti-CD40-induced IgE secretion, germline and mature epsilon transcripts, and epsilon germline promoter activation. Interleukin-4 plus anti-CD40 increased intracellular cAMP by activating cAMP-synthesizing adenylate cyclase in surface IgE- B cells, and the increase was greater in the cells from atopic dermatitis patients than in those from normal donors. Ketoconazole suppressed interleukin-4 plus anti-CD40-induced activation of adenylate cyclase in surface IgE- B cells. These results suggest that ketoconazole may suppress interleukin-4 plus anti-CD40-induced B cell IgE class switching by inhibiting cAMP signal, and stress its prophylactic effects on allergic diseases.

Adenylyl Cyclases↗

PubMed1999

Two differently regulated nuclear factor kappaB activation pathways triggered by the cytoplasmic tail of CD40.

CD40 signaling modulates the immune response at least in part by activation of nuclear factor kappaB (NFkappaB). It has been shown that two distinct domains in the CD40 cytoplasmic tail (cyt), namely cyt-N and cyt-C, independently activate NFkappaB. Although four members of the tumor necrosis factor receptor-associated factor (TRAF) family, including TRAF2, TRAF3, TRAF5, and TRAF6, bind to the CD40 cyt, how each TRAF protein contributes to the NFkappaB activation by CD40 is not clear. Here we report that TRAF2, TRAF3, and TRAF5 bind cyt-C, whereas TRAF6 binds cyt-N. cyt-N is conserved poorly between human and mouse CD40, while cyt-C is highly conserved. However, single aa substitution of Glu-235 in cyt-N of human CD40 with Ala abolishes the binding of TRAF6 to cyt-N and NFkappaB activation by cyt-N. Conservation of this Glu between mouse and human CD40 strongly suggests that TRAF6 could link cyt-N to signals essential for CD40-mediated immune response. Furthermore, NFkappaB activation by cyt-C is inhibited by a kinase-negative form of NFkappaB-inducing kinase more efficiently than that by cyt-N, consistent with the result that NFkappaB activation by TRAF2 and TRAF5 is inhibited by a kinase-negative form of NFkappaB-inducing kinase more efficiently than that by TRAF6. These results indicate that NFkappaB activating signals emanating from cyt-N and cyt-C are mediated by the different members of the TRAF family and could be regulated in a distinct manner.

Amino Acid Sequence↗

PubMed1995

Selective activation of c-Jun kinase mitogen-activated protein kinase by CD40 on human B cells.

The B cell surface antigen receptor, surface IgM (sIgM), is involved in B cell activation and proliferation. CD40 is involved in regulating IgE production and B cell survival. Cross-linking of B cell sIgM activates the Ras/Raf/p42erk2 pathway. In contrast, ligation of CD40 by antibody or soluble gp39 (CD40 ligand) leads to activation of the c-Jun kinase (JNK)/stress-activated protein kinase pathway. JNK/stress-activated protein kinase activation correlated with the stimulation of MEK kinase activity. CD40 does not activate the p42erk2 pathway, and sIgM fails to regulate the JNK/stress-activated protein kinase pathway in B cells. Thus, two important cell surface receptors involved in controlling specific B cell response differentially regulate sequential protein kinase pathways involving different members of the mitogen-activated protein kinase family. Anti-CD40 also rescued B cell apoptosis induced by anti-IgM. CD40 ligation did not affect the sIgM stimulation of p42erk2 activity. Conversely, sIgM ligation did not influence CD40 stimulation of JNK/stress-activated protein kinase. These results suggest that independent, parallel protein kinase response pathways are involved in the integration of sIgM and CD40 control of B cell phenotype and function.

Antibodies↗

PubMed2000

Involvement of STAT-1 and ets family members in interferon-gamma induction of CD40 transcription in microglia/macrophages.

Cluster of differentiation (CD)-40 is a cell surface receptor belonging to the tumor necrosis factor receptor family that plays a critical role in the regulation of immune responses. We have previously shown that the cytokine interferon (IFN)-gamma induces CD40 expression in microglia. Herein, we have elucidated the molecular mechanisms underlying IFN-gamma induction of CD40 gene expression in microglia/macrophages. IFN-gamma up-regulates CD40 expression at the transcriptional level, and this regulation involves the STAT-1alpha transcription factor. Microglia from STAT-1alpha-deficient mice were refractive to IFN-gamma induction of CD40 expression, illustrating the importance of STAT-1alpha in this response. Functional analysis of the CD40 promoter indicates that two gamma activated sequence elements as well as two Ets elements are involved in IFN-gamma induction of CD40 promoter activity. STAT-1alpha binds to the gamma activated sequence elements, whereas PU.1 and/or Spi-B bind to the Ets elements. The expression of PU.1 and Spi-B, in conjuction with STAT-1alpha activation, correlates with IFN-gamma inducibility of CD40 expression. Collectively, our data demonstrate the involvement of STAT-1alpha, PU.1, and Spi-B in IFN-gamma induction of CD40 gene expression in cells of the macrophage lineage.

Animals↗

PubMed2003

Synergistic B cell activation by CD40 and the B cell antigen receptor: role of B lymphocyte antigen receptor-mediated kinase activation and tumor necrosis factor receptor-associated factor regulation.

Optimal activation of B-lymphocytes depends both upon expression of various cell surface receptors and adequate integration of signaling pathways. This requires signals generated upon recognition of antigen by the B lymphocyte antigen receptor (BCR) as well as additional signals provided by cognate interaction with T helper cells, including the CD40-CD154 interaction. Engagement of both the BCR and CD40 results in synergistic activation of B cells. Previous studies identified tumor necrosis factor receptor-associated factor (TRAF)-2 and TRAF3 in the CD40-signaling pathway together with BCR-activated protein kinase D (PKD) as important cooperative factors in this synergy. To better understand the role of these factors in bridging the BCR and CD40 signaling pathways, BCR signal regulation of TRAF function was examined. Results show that phosphorylation of TRAF2 is increased upon BCR but not CD40 engagement and that of the potentially phosphorylated residues of TRAF2, tyrosine 484 is crucial for BCR-CD40 synergy. Additionally, wild type or constitutively active Bruton's tyrosine kinase (Btk) enhanced, whereas the xid mutant form of Btk prevented, BCR-CD40 synergy. These effects were dependent upon TRAF2 and PKD activity. These findings suggest a model in which Btk contributes to the enhancement of the CD40 response by TRAF2 in a PKD-dependent manner.

Amino Acid Sequence↗