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CD40 Expression (cd40 + expression)
Selected AbstractsSelective regulation of CD40 expression in murine dendritic cells by thiol antioxidantsIMMUNOLOGY, Issue 2 2003Norifumi Iijima Summary Interaction of CD40 on dendritic cells (DC) with CD40 ligand induces interleukin-12 (IL-12) production by these DC during the antigen presentation. Thus, the level of CD40 expression appears to influence the capability of DC to induce a T helper 1 (Th1) response. However, it is not fully understood how CD40 expression on DC is regulated. In the present study, we examined the effects of the reducing agents, N -acetyl- l -cysteine (NAC) and reduced glutathione (GSH), on tumour necrosis factor-, (TNF-,)-induced phenotypic changes in murine DC. TNF-, markedly increased the expression on DC of major histocompatibility complex (MHC) and the costimulatory molecules, CD40, CD80 and CD86. Both NAC and GSH completely abolished the TNF-,-induced enhancement of CD40 expression, but had no considerable effect on the expression of CD80, CD86 and MHC. The marked decrease of CD40 protein with NAC was also detected by Western blotting, but was not associated with the expression level of CD40 mRNA in DC. Thus, NAC appears to reduce CD40 expression on DC by regulating a post-transcriptional pathway. The inhibitory effect of NAC or GSH on TNF-,-induced CD40 expression was released by simply removing these agents from the culture. In contrast, culture of TNF-,-treated DC with NAC or GSH markedly decreased the expression of CD40 within 12 hr. These results demonstrate that reducing agents selectively, rapidly and reversibly regulate CD40 expression on DC, which may eventually affect the capability of DC for Th1/Th2 polarization. [source] The proportion of CD40+ mucosal macrophages is increased in inflammatory bowel disease whereas CD40 ligand (CD154)+ T cells are relatively decreased, suggesting differential modulation of these costimulatory molecules in human gut lamina propriaINFLAMMATORY BOWEL DISEASES, Issue 11 2006Dr. Hege S. Carlsen MD Abstract Background: Signal transduction through binding of CD40 on antigen-presenting cells and CD40 ligand (CD154) on T cells appears to be crucial for mutual cellular activation. Antibodies aimed at blocking the CD40,CD154 costimulatory pathway dampen the severity of experimental colitis. To elucidate the microanatomical basis for signaling through this costimulatory pathway in human inflammatory bowel disease, we studied in situ the cellular distribution of these 2 molecules on lamina propria macrophages and T cells, respectively. Methods: Colonic specimens from 8 patients with ulcerative colitis and 8 with Crohn's disease, 8 small bowel specimens of Crohn's disease, and histologically normal control samples (6 from colon and 6 from small bowel) were included. Multicolor immunofluorescence in situ staining was performed to determine the percentage of subepithelial macrophages expressing CD40 and that of lamina propria T cells expressing CD154 while avoiding cells in lymphoid aggregates. Results: The proportion of subepithelial CD40highCD68+ macrophages was significantly increased in normal colon compared with normal small bowel and showed further elevation in both colon and small bowel afflicted with inflammatory bowel disease. In addition, on a per-CD68+ -cell basis, CD40 expression was significantly increased in severely inflamed compared with moderately inflamed colonic specimens. Conversely, the proportion of CD154+ T cells was similar in colon and small bowel, and interestingly, it was significantly reduced in colonic inflammatory bowel disease. Conclusions: Our findings suggested that modulation of CD40 expression by subepithelial macrophages and CD154 by lamina propria T cells is inversely modulated in the human gut. [source] Expression of RANTES and MCP-1 in epithelial cells is regulated via LMP1 and CD40INTERNATIONAL JOURNAL OF CANCER, Issue 12 2007Maike Buettner Abstract Epstein-Barr virus (EBV)-associated undifferentiated nasopharyngeal carcinoma (NPC) is characterized by a prominent nonneoplastic lymphoid stroma. The functional role of these inflammatory cells and the mechanism of their recruitment are not fully understood. In B-cells, the EBV-encoded latent membrane protein 1 (LMP1) can induce the expression of chemokines in an NF-,B dependent manner. We now show that LMP1 can induce the expression of RANTES and MCP-1 in an epithelial cell line, and that this effect is partially reversible by an inhibitor of NF-,B. Since tumor cells of virtually all NPCs show CD40 expression while many cases are LMP1-negative at the protein level, we also investigated the effect of CD40 signaling and demonstrate that CD40 stimulation can transiently induce RANTES and MCP-1 expression in LMP1-negative epithelial cells. In in situ hybridization only rare tumor cells showed expression of these chemokines unrelated to LMP1 expression, a pattern consistent with transient induction through CD40 signaling. Since RANTES and MCP-1 were also detected in the neoplastic cells of oral squamous cell carcinomas lacking a lymphoid stroma it remains uncertain to what extent these CC chemokines contribute to the attraction of inflammatory cells into the NPC microenvironment. © 2007 Wiley-Liss, Inc. [source] CD40 and OX40 ligand are differentially regulated on asthmatic airway smooth muscleALLERGY, Issue 7 2009D. I. Krimmer Background:, CD40 and OX40 Ligand (OX40L) are cell-surface molecules expressed on airway smooth muscle (ASM) that can enhance inflammatory cell activation and survival. The aim of this study was to examine the effect of tumour necrosis factor-alpha (TNF-,) and interferon-gamma (IFN-,) on ASM CD40 and OX40L expression. Methods:, CD40 and OX40L expression on human ASM cells from asthmatic and nonasthmatic donors following stimulation with TNF-, and/or IFN-, was measured using cell-surface enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Involvement of signalling pathway was investigated with pharmacological inhibitors. Soluble TNF receptor levels were quantified by ELISA. Results:, Interferon-, and TNF-, synergistically increased CD40 expression to a greater extent on asthmatic than on nonasthmatic ASM. In contrast, IFN-, reduced TNF-,-induced OX40L expression to a similar extent in both cell types. TNF-, and IFN-, induced CD40 via nuclear factor-,B (NF-,B) and signal transducer and activator of transcription-3 in both cell types and modulated OX40L via NF-,B and c-Jun N terminal kinase in nonasthmatic cells. Similar effects on the induction of OX40L in asthmatic cells were seen with NF-,B, but these were not statistically significant. The reduced OX40L expression with TNF-, and IFN-, involved extracellular regulated kinase 1/2 activation. Conclusion:, Asthmatic ASM may modulate airway inflammation locally by increasing CD40 and OX40L expression in response to cytokines. IFN-, may regulate ASM pro-inflammatory actions by differentially modulating ASM CD40 and OX40L expression. [source] Inhibition of allergic responses by CD40 gene silencingALLERGY, Issue 3 2009M. Suzuki Background:, Gene silencing using small interfering RNA (siRNA) is a potent method of specifically knocking down molecular targets. Small interfering RNA is therapeutically promising, however, treatment of allergic diseases with siRNA has not been explored in vivo. The aim of this study was to evaluate therapeutic effects of CD40 siRNA on inhibition of allergic responses. Methods:, Mice sensitized with ovalbumin (OVA) and alum were treated with CD40 siRNA, scrambled siRNA, or phosphate buffer saline (PBS) alone, and then challenged intranasally with OVA. Results:, A significant reduction in nasal allergic symptoms was observed in the CD40 siRNA treated OVA-allergic mice compared to the controls of scrambled siRNA and PBS alone, which is correlated with the decrease of local eosinophil accumulation. CD40 siRNA treatment knocked down CD40 expression on dendritic cells (DCs) in vivo and impaired their antigen presenting function. Treatment with CD40 siRNA resulted in inhibition of OVA-specific T cell response and decrease of interleukin-4 (IL-4), IL-5, and interferon-, production from T cells stimulated with OVA. Administration of CD40 siRNA also suppressed CD40 expression on B cells, resulting in down-regulation of OVA-specific immunoglobulin E (IgE), IgG1, and IgG2a levels. Additionally, increased regulatory T cells were observed in the CD40 siRNA treated mice. Conclusions:, The present study demonstrates a novel therapeutic use for siRNA in allergy. CD40 siRNA attenuated allergy through inhibition of DC and B cell functions and generation of regulatory T (Treg) cells. [source] Filaria/Wolbachia activation of dendritic cells and development of Th1-associated responses is dependent on Toll-like receptor 2 in a mouse model of ocular onchocerciasis (river blindness)PARASITE IMMUNOLOGY, Issue 9 2007K. DAEHNEL SUMMARY Toll-like receptors (TLRs) regulate dendritic cell function and activate signals that mediate the nature of the adaptive immune response. The current study examined the role of TLRs in dendritic cell activation and in regulating T cell and antibody responses to antigens from the filarial parasites Onchocerca volvulus and Brugia malayi, which cause river blindness and lymphatic filariasis, respectively. Bone-marrow-derived CD11c+ cells from C57BL/6 and TLR4,/, mice produced high levels of IL-6 and RANTES, and showed elevated surface CD40 expression, whereas CD11c+ cells from myeloid differentiation factor 88,/, (MyD88,/,), TLR2,/, and TLR2/4,/, mice were not activated. Similarly, IFN-, production by splenocytes from immunized TLR2,/, mice was significantly impaired compared with splenocytes from C57BL/6 and TLR4,/, mice. In contrast, there was no difference among these strains in Th2-associated responses including IL-5 production by splenocytes from immunized animals, serum IgE and IgG1, or eosinophil infiltration into the corneal stroma. Neutrophil recruitment to the cornea and CXC chemokine production was inhibited in immunized TLR2,/, mice compared with C57BL/6 and TLR4,/, mice. Taken together, these findings demonstrate an essential role for TLR2 in filaria-induced dendritic cell activation, IFN-, production and neutrophil migration to the cornea, but does not affect filaria-induced Th2-associated responses. [source] Pooled Human Gammaglobulin Modulates Surface Molecule Expression and Induces Apoptosis in Human B CellsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 2 2003Mieko Toyoda We have previously shown that the pooled human gammaglobulin (IVIG) inhibited mixed lymphocyte reaction (MLR). In this study, we examined (1) if IVIG contains blocking antibodies reactive with cell surface molecules required for alloantigen recognition and (2) if IVIG modulates these surface molecule expressions using flow cytometry. IVIG does not contain significant amounts of blocking antibodies against CD3, CD4, CD8, CD20, CD14, CD40, MHC class I and class II. It reduces the number of intact B cells and monocytes, reduces or modulates CD19, CD20 and CD40 expression on B cells, and induces morphological changes in B cells. This B-cell modulation results primarily because of apoptosis. IVIG also induces apoptosis in T cells and monocytes, but to a lesser degree. Induction of apoptosis requires the intact IgG molecule. Reduction of intact B cell and monocyte cell numbers, modulation of surface molecule expression on B cells, and deletion of B and T cells by apoptosis could result in inhibition of optimal T-cell activation. This likely represents the primary mechanism responsible for IVIG suppression of the MLR, and may account for many of the observed beneficial effects of IVIG seen in the treatment of human autoimmune and alloimmune disorders. [source] Up-regulation of CD40 with juxtacrine activity in human nonsmall lung cancer cells correlates with poor prognosisCANCER, Issue 3 2008Keidai Ishikawa MD Abstract BACKGROUND. CD40 and its ligand, CD154, play a regulatory role in several signaling pathways among lymphocytes. Recently, it was reported that CD40 is expressed in several malignant tumors. However, the clinical impact of CD40 expression in nonsmall cell lung cancer has not been studied widely. METHODS. One hundred twenty-nine surgical specimens of nonsmall cell lung cancer were assessed immunohistochemically for CD40 and CD154 expression, and that expression was correlated with patients' clinicopathologic parameters and outcome. Subsequently, in vitro analysis of CD40-CD154 signaling was performed. RESULTS. Immunohistochemical staining of tumor cells confirmed that 67 patients (51.9%) were positive for CD40, and 76 patients (58.9%) were positive for CD154. The survival of patients who had tumors that were negative for CD40 was significantly better than the survival of patients who had tumors that were positive for CD40 (P = .0004). Multivariate analysis using a Cox regression model indicated that CD40 expression in cancer cells is an independent, unfavorable prognostic factor (risk ratio, 1.855; P = .0403). By using an in vitro juxtacrine growth factor assay, the growth of LK2 cells (CD40-positive/CD154-negative) was accelerated by CD154-positive cancer cells, such as PC10 cells (CD40-negative/CD154-positive), by a juxtacrine mechanism. CONCLUSIONS. The current results suggested that CD40 expression in tumors is associated with a poor prognosis and that the juxtacrine interaction of CD40-CD154 among cancer cells facilitates the development of malignant potential in nonsmall cell lung cancer. Cancer 2008. © 2008 American Cancer Society. [source] Transfection and ligation of CD40 in human oral keratinocytes affect proliferation, adhesion and migration but not apoptosis in vitroCLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 2 2006M. Villarroel Dorrego Summary Aims:, CD40 expression is restricted to Keratinocytes of normal epidermis or stratified squamous epithelium of oral mucosa. Ligation of CD40 inhibits keratinocyte proliferation and apoptosis. The aim of this study was to investigate the functional significance of CD40 in the proliferation, apoptosis, adhesion and migration of human oral keratinocytes in vitro. Methods., The CD40-negative oral keratinocyte line OSC19, its CD40-positive transfected derivative (OSC19T-CD40) and null transfectants (OSC19T-control), with and without stimulation by soluble protein CD40 ligand (sCD40L) or anti-CD40 antibodies were used. Results., OSC19T-CD40 showed significantly (P < 0.001) slower growth than the null transfectants and parent cells. OSC19T-CD40 proliferation was inhibited by ligation with sCD40L and blocking by two anti-CD40 antibodies, but stimulated by a third. Binding of CD40 with ligand or antibody had no effect on keratinocyte apoptosis in any cell line. The capacity of OSC19T-CD40 cells to adhere to CD40L-coated wells was significantly greater (P < 0.001) than that of parent OSC19 and OSC19T-control cells, and the migration rate of OSC19T-CD40 cells was significantly higher than parent OSC19 (P = 0.038 on fibronectin, P = 0.004 on Matrigel) or OSC19T-control (P =0.017 on fibronectin, P = 0.013 on Matrigel) cells. Conclusions., CD40 is an important molecule in keratinocyte homeostasis, and has more than one ligand. The ligand that is bound may be critical in oral epithelial homeostasis, the development of malignancy and the behaviour of the subsequent tumour. [source] | ||||||||||||||||||||||