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At least 631 records · Page 35Linked to original sources
PubMed2003

CD40 triggering enhances fludarabine-induced apoptosis of chronic lymphocytic leukemia B-cells through autocrine release of tumor necrosis factor-alpha and interferon-gama and tumor necrosis factor receptor-I-II upregulation.

BACKGROUND AND OBJECTIVES: In chronic lymphocytic leukemia (CLL) B-cells are refractory to activation signals and to apoptosis. CD40 triggering, however, rescues CLL B-cells from their anergic state and upregulates the FAS receptor. We therefore studied whether CD40 triggering enhances CLL B-cell sensitivity to fludarabine, and receptors or cytokines potentially involved in apoptosis. DESIGN AND METHODS: CD40-activation of CLL B-cells was carried out by co-culture with CD40L-transfected cells. After fludarabine treatment, apoptosis was evaluated by propidium iodide (PI), annexin-V/PI or DiOC6 staining and flow cytometry analysis. Modulation of Bcl-2, of tumor necrosis factor receptor (TNFRI/II) and release of tumor necrosis factor (TNF)alpha/interferon (IFN)gamma was also analyzed. Furthermore, addition of caspase-inhibitors or anti-TNFalpha/-IFNgamma monoclonal antibodies to fludarabine-treated cells allowed us to determine the mediators of apoptosis. Student's t tests or ANOVA variance statistical analysis were performed to evaluate whether any differences observed might be considered significant. RESULTS: CD40 triggering enhanced fludarabine sensitivity of CLL B-cells, downmodulated Bcl-2 and upregulated TNFRI/II. Caspases 1 and 6 were the major caspases involved in fludarabine apoptosis induction in resting B cells, while only anti-TNFalpha/-IFNgamma monoclonal antibodies reduced apoptosis in activated cells. In agreement with this observation, autocrine production of TNFalpha and IFNgamma by CD40-activated CLL B cells was found. INTERPRETATION AND CONCLUSIONS: B-cells from a considerable proportion of CLL cases studied (11/20) are more prone to fludarabine-induced apoptosis after CD40 triggering; accordingly Bcl-2 expression was lower in activated cells. Moreover, upregulation of TNFRI/II, release of TNFalpha and IFNgamma, and inhibition of apoptosis by anti-TNFalpha/-IFNgamma monoclonal antibodies in CD40-activated cells strongly suggest that these cytokines may play a role in sensitizing B-cells to fludarabine treatment.

Aged↗
PubMed2004

Increased CD40 expression on articular chondrocytes from patients with rheumatoid arthritis: contribution to production of cytokines and matrix metalloproteinases.

OBJECTIVE: To examine expression of CD40 on articular chondrocytes derived from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) and to investigate roles of CD40 on articular chondrocytes in production of inflammatory mediators associated with degradation of articular cartilage. METHODS: Articular cartilage samples were obtained from patients with RA and OA at total knee arthroplasty. Expression of CD40 on chondrocytes was examined using immunohistochemistry, reverse transcriptase-polymerase chain reaction (RT-PCR), and flow cytometry. Tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), matrix metalloproteinase (MMP)-3, and tissue inhibitor of matrix metalloproteinase (TIMP)-1 in culture supernatants of chondrocytes were measured by ELISA. RESULTS: Immunohistochemical staining revealed that CD40 was expressed on RA chondrocytes in vivo, but not in OA chondrocytes. RT-PCR and flow cytometry showed that cultured articular chondrocytes from RA patients, but not from OA patients, constitutively expressed CD40, and that interferon-gamma (IFN-gamma) enhanced the expression of CD40 on chondrocytes from both RA and OA patients. Membrane fraction of mouse myeloma Ag8 cells that was transfected with human CD154 (Ag8-hCD154) induced production of TNF-alpha, IL-6, and MMP-3 in RA chondrocytes, and pretreatment of RA chondrocytes with IFN-gamma enhanced the response. OA chondrocytes did not respond to stimulation with the membrane fraction of Ag8-hCD154 cells alone, but the cells did produce TNF-alpha, IL-6, and MMP-3 after pretreatment with IFN-gamma. CONCLUSION: CD40-CD154 interaction augments the expression of inflammatory cytokines and MMP in chondrocytes and contributes to an intrinsic process of cartilage degradation in RA.

Animals↗
PubMed2005

[Liposome-mediated human CD40 gene transfection and human umbilical vein endothelial ECV-304 cells].

OBJECTIVE: To construct an eukaryotic expression vector containing human CD40 gene for its efficient, continuous and stable expression in human umbilical vein endothelial ECV-304 cells. METHODS: The recombinant plasmid pUCD40 was digested with endonucleases to obtain human CD40 gene fragment, which was cloned into pCDNA3.1 vector to construct recombinant eukaryotic expression vector pCDNA3.1(+)/CD40. The recombinant vector was identified by enzyme digestion before introduced into ECV-304 cells via liposome, with the positive cell clones selected with G418. The stable transfection and expression of CD40 in ECV-304 cells were identified by reverse transcription (RT)-PCR, Western blotting and flow cytometry, respectively. RESULTS: Enzyme digestion analysis showed that target gene had been cloned into the recombinant vector. The transfected ECV-304 cells successfully expressed human CD40 as determined by RT-PCR and Western-blotting, and 95% of the cells were CD40-positive as shown by flow cytometry. CONCLUSION: The recombinant eukaryotic expression vector pCDNA3.1(+)/CD40 has been successfully constructed, which is capable of stable transfection and expression of CD40 in ECV-304 cells to facilitate further investigation of the roles of CD40 molecule in antiatherosclerotic drug development.

CD40 Antigens↗
PubMed1994

CD40 molecules induce down-modulation and endocytosis of T cell surface T cell-B cell activating molecule/CD40-L. Potential role in regulating helper effector function.

The T-BAM/CD40-L molecule on CD4+ T cells interacts with B cell CD40 molecules to deliver contact-dependent signals that drive B cell activation and Ig secretion. Cell surface T-BAM/CD40-L expression is transient and may be closely regulated in order to limit the activation and clonal selection of noncognate B cells. We demonstrate that B cells, but not non-B cells, rapidly and specifically down-modulate surface T-BAM/CD40-L expression in a contact-dependent and temperature-sensitive manner that renders T cells unable to activate resting bystander B cells. Because the ability to down-modulate T-BAM/CD40-L correlated with CD40 expression, the role of CD40 molecules in down-modulating its ligand was directly assessed. Anti-CD40 mAb, but not control mAb, block B cell-induced T-BAM/CD40-L down-modulation. Furthermore, CD40+ nonlymphoid transfectants specifically down-modulate surface T-BAM/CD40-L expression. B cells induce T-BAM/CD40-L internalization into cytoplasmic compartments in a process that is inhibited by cytochalasin B. Pretreatment of activated T cells with lysosomotropic agents does not affect CD40-induced down-modulation of surface T-BAM/CD40-L but results in a marked accumulation of T-BAM/CD40-L in cytoplasmic vesicles. Together, these studies strongly suggest that CD40 induced T-BAM/CD40-L down-modulation occurs, in part, by receptor-mediated endocytosis followed by lysosomal degradation and may represent a mechanism to regulate CD4+ T cell helper effector functions.

Amino Acid Sequence↗
PubMed1995

Stimulation of CD40 with purified soluble gp39 induces proinflammatory responses in human monocytes.

CD40 is a glycoprotein of about 50 kDa that plays a crucial role in B cell growth and differentiation. It is found on the surface of B cells, follicular dendritic cells, monocytes, and some endothelial, epithelial, and carcinoma cells. Engagement of CD40 with anti-CD40 mAbs, gp39 expressed on the cell surface or soluble forms of gp39, primes B cells to efficiently respond to subsequent stimulatory signals leading to B cell proliferation, differentiation, and isotype switching. Peripheral monocytes also express CD40 on the cell surface and expression in increased following treatment with IFN-gamma. Using a soluble murine CD8/human gp39 fusion protein (sgp39) we have found that CD40 plays a crucial role in the regulation of monocyte function. Stimulation of human peripheral monocytes with sgp39 induced homotypic aggregation and significantly increased the expression of several cell-surface proteins including CD54, MHC class II, CD86, and CD40. Soluble gp39 also dramatically enhanced monocyte survival, preventing the onset of apoptosis that normally occurs upon withdrawal of serum. Finally, in the absence of any costimulatory molecules, sgp39 stimulated monocytes to produce TNF-alpha, IL-1 beta, IL-6, and IL-8. These results suggest that ligation of CD40 on human monocytes induces phenotypic changes that would be expected to influence T cell activation by the monocyte and also to enhance or prolong inflammatory responses.

Animals↗
PubMed1993

The regulation of T cell-dependent antibody formation in vitro by CD40 ligand and IL-2.

Our study demonstrates the central role for the murine CD40 ligand and IL-2 in contact-dependent T cell help for Ag-specific primary antibody responses in vitro. Helper T cell clones were found to express CD40 ligand after activation with CD3 mAb. Membrane-bound recombinant CD40 ligand expressed on fixed CV1/EBNA cells had similar B cell-activating properties as T cell clones that had been activated and then fixed. These activities include the induction of B cell proliferation, induction of polyclonal secretion of multiple Ig isotypes in a cytokine-dependent manner, and induction of Ag-specific antibody responses by purified B cells. The induction of polyclonal Ig secretion by the recombinant CD40 ligand required IL-4 and IL-5 although optimal Ag-specific antibody formation required IL-2. Finally, soluble CD40.Fc inhibited the induction of Ag-specific antibody responses by fixed, activated Th cell clones. The requirement for both CD40 ligand and IL-2 for induction of Ag-specific antibody responses was mediated, in part, by the induction of B cell IL-2R expression by CD40 ligand. We conclude that the interaction of CD40 on B cells with its ligand on activated T cells is an integral event in the early activation of B cells to grow and differentiate to antibody formation.

Animals↗
PubMed1996

Isolation and characterization of murine fra-1: induction mediated by CD40 and surface Ig is protein kinase C dependent.

The murine fra-1 gene, encoding Fos-related Ag 1, was isolated from a splenic cDNA library and sequenced. Murine fra-1 was highly homologous to rat and human fra-1. Oligonucleotide primers based on the murine sequence were used to construct a quantitative reverse transcription-PCR assay for gene expression. B lymphocyte stimulation via both CD40 and surface Ig (sIg) receptors substantially induced fra-1 expression, and for both receptors, induction was protein kinase C (PKC) dependent. This contrasts with induction of c-fos by both CD40 and sIg, which is PKC independent and indicates that CD40 is capable of signaling through PKC or a closely related kinase. Induction of fra-1 following engagement of CD40 did not require protein synthesis, suggesting that the PKC-dependent linkage between CD40 and fra-1 is direct. CD40-mediated fra-1 induction did require tyrosine kinase activity. These results demonstrate that CD40, like sIg, may employ PKC in producing select outcomes, that individual B cell receptors may signal downstream events via both PKC-dependent and PKC-independent pathways, and that multiple signal transduction pathways may be used to activate the expression of closely related genes.

Animals↗
PubMed1997

CD40 is a functional activation antigen and B7-independent T cell costimulatory molecule on normal human lung fibroblasts.

CD40 is an important signaling and activation Ag found on certain bone marrow-derived cells. Recently, CD40 also has been shown to be expressed by mesenchymal cells, including human fibroblasts. Little is known about the role of CD40 in fibroblasts. The current study investigates the hypothesis that CD40 expressed on lung fibroblasts is an activation structure and mechanism for interaction with hemopoietic cells. Communication between resident tissue fibroblasts and T cells is necessary for normal wound healing, and can be pathologic, resulting in tissue fibrosis. Signaling through CD40 with soluble CD40 ligand stimulated fibroblast activation, as evidenced by mobilization of nuclear factor-kappaB and by induction of the proinflammatory and chemoattractant cytokines IL-6 and IL-8. IFN-gamma-primed lung fibroblasts costimulate T lymphocyte proliferation utilizing CD40, but not the well-studied costimulatory molecules B7-1 and B7-2. Data reported herein support the hypothesis that cognate interactions between tissue fibroblasts and infiltrating T lymphocytes, via the CD40/CD40L pathway, augment inflammation and may promote fibrogenesis by activating both cell types.

B7-1 Antigen↗
PubMed1999

CD40 expression in bladder cancer.

The CD40 receptor is expressed in many immune cell types and is known to play a central role in both humoral and T-cell-mediated immunity, being a subject of intense research interest in recent years. It is also expressed on a variety of carcinomas and may therefore be of biological significance in the development and treatment of cancer. The expression of CD40 was examined immunohistochemically in a series of 131 bladder transitional cell carcinomas and the correlation with known prognostic markers and clinical outcome assessed. Seventy-eight per cent of the tumours were CD40-positive, with a highly significant association with both lower stage and lower grade (p<0.001). Ta and T1 tumours expressed CD40 in 89 per cent of specimens compared with 62 per cent seen in T2-T4 tumours and in contrast to normal urothelium, which was mainly CD40-negative. CD40 expression was not related to any other clinicopathological variable including Bcl-2 and p53 expression, nor was it an independent prognostic marker. The lack of the relationship with Bcl-2 staining which is normally seen in basal epidermal cells may indicate alternative or abnormal CD40-mediated cell differentiation mechanisms. The diffuse expression seen in Ta bladder tumours may account for its clinically less aggressive behaviour and is likely to be an important factor in the excellent clinical response seen to BCG immunotherapy. It also raises the possibility of the future development of CD40/CD40 ligand-based immunotherapy for bladder cancer.

Adult↗
PubMed1999

CD40 and Bcl2 expression in squamous cell carcinoma of the lung: correlation with apoptosis, survival, and other clinicopathological factors.

CD40 is a cell surface receptor which, when ligated, modulates apoptosis in some cell types, perhaps via activation of the expression of members of the Bcl2 gene family. This study sought to determine whether expression of CD40 in a series of 134 squamous cell carcinomas (SCCs) of the lung was related to apoptosis or clinical parameters, either alone or in connection with Bcl2 expression. Sections of SCCs were stained for CD40 and Bcl2 by immunohistochemical techniques. An index was determined for these two markers by counting stained and unstained malignant cells under high power. Sections were also stained by haematoxylin and eosin for determination of the apoptotic index by counting apoptotic bodies. About 40 per cent of SCCs expressed CD40 in at least some of the malignant cells, with about 10 per cent essentially uniformly stained. Similar proportions expressed Bcl2, with a tendency for expression to be mutually excluisve. Apoptosis did not correlate with CD40 expression, nor was there evidence of a co-operative or an antagonistic effect with Bcl2. Bcl2 expression, on the other hand, correlated significantly with the apoptosis score. CD40 expression showed no significant relationship with survival or any other clinicopathological parameter except ploidy. Bcl2 expression, however, correlated with longer survival. It is concluded that CD40 expression in SCC of the lung does not by itself relate to apoptosis, nor is it a useful indicator of prognosis.

Adult↗
PubMed1998

The induction of a protective response in Leishmania major-infected BALB/c mice with anti-CD40 mAb.

A protective immune response to the intracellular parasite Leishmania major requires the development of a Th1 CD4+ T cell phenotype. We demonstrate herein that BALB/c mice, which normally develop a susceptible Th2 response to L. major infection, are protected when co-injected with an agonistic anti-murine CD40 mAb. Anti-CD40 mAb-mediated protection in this system was found to be T cell dependent, since it was not observed in C57BL/6 x 129 mice that were rendered T cell deficient (TCR beta-/- x TCR delta-/-) and L. major susceptible. Anti-CD40 mAb stimulation of L. major-infected BALB/c mice was accompanied by increased IL-12 and IFN-gamma production in draining lymph nodes, analyzed either by direct expression, or in an antigen-specific in vitro recall assay. The protective role of these cytokines was indicated by the finding that anti-CD40 mAb-mediated protection of L. major-infected BALB/c mice could be reversed by co-treating the animals with neutralizing anti-IL-12 and/or anti-IFN-gamma mAb. Collectively, these data suggest that BALB/c mice develop a protective Th1 CD4+ T cell response to L. major infection when co-injected with anti-CD40 mAb. While the CD40-CD40L interaction has been previously shown to be vital in the control of murine Leishmaniasis, the current study establishes in vivo that anti-CD40 mAb treatment alone is sufficient to protect BALB/c mice from L. major infection and raises the possibility of utilizing this approach for vaccination strategies.

Animals↗
PubMed2000

Early myeloid cells are high producers of nitric oxide upon CD40 plus IFN-gamma stimulation through a mechanism dependent on endogenous TNF-alpha and IL-1alpha.

Bone marrow contains nonadherent low-density wheat germ agglutinin-positive (Fr3-WGA(+)) cells that release large amounts of NO and show natural suppressor activity if stimulated with activated T cells. We have assessed the involvement of CD40-derived signals in NO production and their cytokine requirements. Production of NO by Fr3-WGA(+) cells in co-culture with activated T cells is inhibited by a competing CD40 soluble fusion protein. Fr3-WGA(+) cells express the inducible NO synthase (iNOS) and release NO following CD40 plus IFN-gamma activation. Production of NO through CD40 is strictly dependent on endogenous TNF-alpha and / or IL-1alpha, since it is inhibited by neutralizing these cytokines or blocking the TNF receptor (p55). Both cytokines are transcribed when Fr3-WGA(+) cells are stimulated by CD40 signaling plus IFN-gamma, although TNF-alpha remains below detection limits in stimulated Fr3-WGA(+) cell cultures. Phenotypic studies combined with data on intracellular iNOS expression and cell sorting indicate that NO-producing cells are CD40, CD31 (ER-MP12), CD11b (Mac-1)low, ER-MP20 (Ly-6C) and Gr-1 (Ly-6G) positive, consistent with myeloid progenitors. The results point to early myeloid cells as an important cell source of NO once triggered by activated T cells through CD40 and IFN-gamma-derived signals, in a mechanism involving the production of TNF-alpha and / or IL-1alpha.

Animals↗
PubMed2002

Protection of marmoset monkeys against EAE by treatment with a murine antibody blocking CD40 (mu5D12).

CD40-CD40 ligand interactions are crucial to cognate interactions between T cells, B cells and antigen-presenting cells (APC), and contribute to non-antigen-specific effector functions of APC in inflammatory disorders. Here we demonstrate that functional blockade of CD40 with an antagonist mouse anti-human CD40 monoclonal antibody (mAb mu5D12) effectively prevents clinical expression of chronic demyelinating experimental autoimmune encephalomyelitis (EAE) in outbred marmoset monkeys, a preclinical model of multiple sclerosis. Anti-CD40 mAb interfered with development of clinical symptoms of marmoset EAE during the treatment period, even when treatment was started several weeks after T cell priming. Magnetic resonance imaging demonstrated inflammatory activity in the brain at initiation of antibody treatment, confirming that treatment interfered with the disease process. Access of therapeutic anti-CD40 to potential sites of action, the secondary lymphoid organs and the brain white matter lesions, was visualized in situ. The present data are the first to demonstrate the clinical potential of blocking APC and effector cell functions using murine antagonist anti-CD40 mAb in the treatment of chronic inflammatory diseases.

Animals↗
PubMed2002

1alpha,25-dihydroxyvitamin D3 inhibits anti-CD40 plus IL-4-mediated IgE production in vitro.

In the present study, we examined whether anti-CD40+IL-4-mediated B cell proliferation and immunoglobulin synthesis is affected by vitamin D (VD) and its low-hypercalcemic analogue EB1089 in Bcells from healthy donors. Analysis of vitamin D receptor (VDR) expression showed that only anti-CD40+IL-4-stimulated, but not resting B cells express VDR. Studies on B cell proliferation revealed that anti-CD40+IL-4-mediated proliferation of B cells was not affected by VD or EB1089. By contrast, IgE synthesis was markedly inhibited by both, VD and EB1089, starting at concentrations from 10(-10) M for VD and 10(-12) M for EB1089, with maximal inhibition at 10(-6) M (VD 85.5+/-9.7%; EB1089 77.3+/-10.8%). The production of the other Ig (IgA and IgG) was not significantly inhibited by VD after anti-CD40+IL-4 stimulation, and IgM production was only slightly reduced (18.7+/-7.9%). These observations were confirmed by intracellular staining of the different isotypes in B cells after anti-CD40+IL-4 stimulation, which showed a strong reduction of IgE(+) cells in the presence of VD. Analyses of molecules that are known to affect IgE production (CD23 and IL-6) revealed that these are not involved in VD-dependent inhibition of IgE production. By contrast, epsilon germ-line transcription was inhibited by VD (41.2+/-26.1%; n=5), as was NF-kappaB (p50 and p65) protein expression in stimulated cells. These data show that VD and its analogue EB1089 inhibit IgE production of anti-CD40+IL-4-stimulated B cells in vitro. The involved mechanism includes epsilon germ-line transcription, NF-kappaB activation and switch recombination suggesting that complex mechanisms of VD action in anti-CD40+IL-4-stimulated B cells are responsible.

B-Lymphocytes↗
PubMed1989

Activation of human B lymphocytes through CD40 and interleukin 4.

We have produced and characterized a new CD40 monoclonal antibody, mAb 89, which in the presence of anti-IgM antibodies co-stimulates to induce B cell proliferation. mAb 89 activates resting B cells as shown by an increase in cell volume and an enhanced subsequent proliferation of B cells in response to anti-IgM antibody. However, mAb 89 does not prepare B cells to respond to the growth-promoting activity of interleukin (IL) 2 or IL 4. Unlike IL 2 and IL 4, mAb 89 only weakly stimulates the proliferation of anti-IgM pre-activated B cells. Thus, the activating properties of anti-CD40 are likely to explain its co-stimulatory effect on B cells. Interestingly, the anti-CD40 mAb 89 was found to act in synergy with IL 4, but not with IL 2, in co-stimulation and restimulation assays. In this respect, anti-CD40 does not induce a significant increase of B cell surface IL 4 receptors while IL 4, but not IL 2, induces a twofold increase of the CD40 antigen expression. Thus the synergistic interaction between IL 4 and anti-CD40 may be related to the IL 4-dependent increase of CD40 antigen expression.

Antibodies, Monoclonal↗
PubMed1993

Expression of a 32-kDa ligand for the CD40 antigen on activated human T lymphocytes.

To identify the ligand(s) of the human CD40 antigen, a cDNA encoding the extracellular domain of the CD40 antigen was fused to a cDNA encoding the constant region (Fc) of human IgG1. The CD40-Fc fusion protein was able to specifically bind to CD4+ and various CD8+ T cell clones activated with immobilized anti-CD3. The 125I-labeled CD40-Fc fusion protein bound anti-CD3 activated CD4+ T cell clone (MT9) with an equilibrium dissociation constant (Kd) of 10-20 nM. The human CD40-binding protein expressed on the cell surface of activated T lymphocytes is a monomeric protein of approximately 32 kDa. Minor components of 29 kDa and 17 kDa were also detected. A small proportion of CD4+ and CD8+ blood mononuclear T cells activated by anti-CD3 expressed the CD40 ligand but its detection was best observed following depletion of B cells. Addition of B cells to purified T cells abolished the binding of CD40-Fc obtained after anti-CD3 activation.

Antigens, CD↗
PubMed1998

IL-4 and CD40 ligation affect differently the differentiation, maturation, and function of human CD34+ cell-derived CD1a+CD14- and CD1a-CD14+ dendritic cell precursors in vitro.

We examined the effect of interleukin (IL)-4 or CD40 ligation on the differentiation and maturation of CD1a+CD14- and CD1a-CD14+ dendritic cell (DC) precursors. Cord blood CD34+ cells were cultured with granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor alpha (TNF-alpha), to which stem cell factor and Flt-3 ligand were added for 5 days. Phenotypic analysis of DC precursors on culture day 7 showed that CD1a+CD14- cells expressed higher CD11c and CD80 levels and lower CD116/GM-CSFR and CCR-5 levels than their CD1a-CD14+ counterparts. Culturing CD1a+CD14- precursors with GM-CSF and TNF-alpha resulted in DC with heterogeneous CD1a, HLA;SMDR (DR), CD11b, and CD83 expression, 10% of which acquired CD14. IL-4 and CD40 ligation affected their differentiation in contrasting ways: IL-4 induced CD1ahiCD14-DRloCD11b+CD83-S100+ DC with reduced MLR-stimulating capacity, whereas CD40 ligation led to CD1alo/-CD14-CD40-DRhiCD11b-CD83+S100+/- DC with stronger MLR-stimulating capacity. Also, both IL-4 and CD40 ligation promoted ReIB expression and nuclear translocation. When CD1a-CD14+ precursors were maintained in only the presence of GM-CSF and TNF-alpha, this led to mixed populations of adherent macrophages and nonadherent CD1a-CD14+ monocytes, and of CD1a+CD14- and CD1a+CD14+ DC, which were DRloCD11b+CD83-S100-. IL-4 or CD40 ligation prevented their differentiation into macrophages and resulted in DC with phenotypes close to those issued from CD1a+CD14- precursors, with only a minority staying CD14+ but most being S100-; their MLR-stimulating capacity also increased but remained lower than that of DC differentiated from CD1a+CD14- precursors. Thus, IL-4 or CD40 ligation induced CD1a+CD14- and CD1a-CD14+ DC precursors to differentiate into phenotypically close but functionally different DC populations, suggesting that DC function is primarily determined by their origin. The heterogeneity of DC should then be related to different developmental pathways and to different stages of maturation/activation.

Antigens, CD1↗
PubMed1997

Role for CD40-mediated activation of c-Rel and maintenance of c-myc RNA levels in mitigating anti-IgM-induced growth arrest.

CD40 crosslinking on B cells activates NF-kappaB and stress-activated protein kinase (SAPK) pathways. Since CD40 crosslinking rescues WEHI 231 B cells from anti-IgM-induced apoptosis, those pathways were likely candidates to be involved. Indeed, both signaling cascades predominated in anti-IgM-treated WEHI 231 cells, treated concurrently with anti-CD40 to rescue them from apoptosis. Crosslinking of CD40 activated the NF-kappaB proteins c-Rel and p50, but had no influence on their cytoplasmic steady state level. However, in contrast to-and even in the presence of-anti-IgM-mediated signals, engagement of CD40 resulted in a prolonged nuclear translocation of c-Rel, thereby allowing the formation of active NF-kappaB complexes. Consistent with this, the upstream regulatory element of the c-myc promoter, known to be regulated by NF-kappaB, was differently regulated after BCR ligation vs BCR plus CD40 crosslinking. The level of c-myc RNA was rapidly downregulated after BCR engagement, but persistent in the presence of CD40 signaling.

Animals↗