Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “CD40”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 613 records · Page 34Linked to original sources
PubMed2002

3-hydroxy-3-methylglutaryl coenzyme A reductase-independent inhibition of CD40 expression by atorvastatin in human endothelial cells.

OBJECTIVE: 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exert potent anti-inflammatory effects that are independent of their cholesterol-lowering action. We have investigated the effects of these drugs on cytokine-stimulated CD40 expression in human cultured endothelial cells and monocytes. METHODS AND RESULTS: Reverse transcription-polymerase chain reaction and Western blot analysis revealed that treatment of either cell type with atorvastatin, cerivastatin, or pravastatin (1 to 10 micromol/L) inhibited interferon-gamma plus tumor necrosis factor-alpha-stimulated CD40 expression by approximately 50%, an effect that was not reversed by the HMG-CoA reductase product mevalonic acid (400 micromol/L). In contrast, mevalonic acid prevented the inhibitory effect of atorvastatin on cytokine-stimulated vascular cell adhesion molecule-1 expression and subsequent adhesion of THP-1 monocytes to the cultured endothelial cells. Transcription factor analysis revealed an inhibition by atorvastatin of nuclear factor-kappaB plus signal transducer and activator of transcription-1-dependent de novo synthesis of interferon regulatory factor-1, governing cytokine-stimulated CD40 expression in these cells. One consequence of this statin-dependent downregulation of CD40 expression was a decrease in CD40 ligand-induced endothelial interleukin-12 expression. CONCLUSIONS: By interfering with cytokine-stimulated CD40 expression in vascular cells, statins thus seem capable of attenuating CD40 ligand-induced proinflammatory responses, including atherosclerosis. In addition, they point to the coexistence of HMG-CoA reductase-dependent and -independent effects of statins in the same cell type.

Atorvastatin↗
PubMed2004

[Involvement of CD40-CD154 interaction in immunopathogenesis of collagen diseases and its application to a novel therapeutic strategy].

CD40 and CD154 belong to the tumor necrosis factor (TNF) receptor superfamily and the TNF superfamily, respectively. Evidence is accumulating that indicates the importance of this receptor-ligand pair in the immunopathogenesis of autoimmune diseases. The CD40-CD154 interaction influences antigen presentation, tolerance, autoantibody production and tissue damage, all of which are relevant to the development and perpetuation of autoimmune diseases. Among the collagen diseases, the CD40-CD154 interaction has been intensively investigated in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). In this article, both basic and clinical research suggesting the involvement of the CD40-CD154 interaction in SLE, RA, inflammatory myopathies, systemic sclerosis and antiphospholipid syndrome are reviewed. The results of clinical trials from CD40-CD154 blockade are also analyzed. CD40-CD154 blockade in animal models of autoimmune diseases has been reported to be a promising novel therapeutic approach and, thus, has attracted great attention from pharmaceutical companies. However, the development of CD40-CD154 blockers with both significant clinical efficacy and safety has not been successful and research advances in this field are eagerly awaited.

Animals↗
PubMed1997

Effects of CD40 stimulation in the prevention of human EBV-lymphomagenesis.

CD40 is a molecule present on B lineage cells, both normal and neoplastic. Signalling through CD40 has been demonstrated to promote B cell growth and differentiation in vitro. In contrast to its effects on normal B cells, we have found that CD40 stimulation can inhibit the growth of various aggressive histology human B cell lymphomas both in vitro and in vivo. Moreover, using a human/mouse chimera model in which human EBV-induced B cell lymphomas can spontaneously arise, we have found that CD40 stimulation an prevent the occurrence of this human lymphoma in mice. However, normal human B cell engraftment and function was not adversely affected in these mice by CD40 stimulation. This indicates that CD40 stimulation is selective in its effects on aggressive histology B cell lymphomas. Thus, CD40 stimulation either by antibody or a recombinant soluble ligand, may be of potential clinical use, not only in the treatment of EBV-induced B cell lymphomas, but also in their prevention.

Animals↗
PubMed2005

Persistence of high CD40 and CD40L expression after restorative proctocolectomy for ulcerative colitis.

AIM: To focus on the role of CD40 and CD40L in their pathogenesis. METHODS: We analyzed by immunohistochemistry the CD40 and CD40L expression in the pouch mucosa of 28 patients who had undergone RPC for UC, in the terminal ileum of 6 patients with UC and 11 healthy subjects. We also examined by flow cytometry the expression of CD40 by B lymphocytes and monocytes in the peripheral blood of 20 pouch patients, 15 UC patients and 11 healthy controls. RESULTS: Ileal pouch mucosa leukocytes presented a significantly higher expression of CD40 and CD40L as compared to controls. This alteration correlated with pouchitis, but was also present in the healthy pouch and in the terminal ileum of UC patients. CD40 expression of peripheral B lymphocytes was significantly higher in patients with UC and pouch, respect to controls. Increased CD40 levels in blood B cells of pouch patients correlated with the presence of spondyloarthropathy, but not with pouchitis, or inflammatory indices. CONCLUSION: High CD40 expression in the ileal pouch mucosa could be implied in the pathogenesis of pouchitis following proctocolectomy for UC, whereas its increased levels on peripheral blood B lymphocytes are associated with the presence of extraintestinal manifestations.

Adult↗
PubMed2000

Prevention of experimental colitis in SCID mice reconstituted with CD45RBhigh CD4+ T cells by blocking the CD40-CD154 interactions.

Increased expression of CD40 and CD40 ligand (CD40L or CD154) has been found in inflamed mucosa of human inflammatory bowel disease (IBD), and interactions between these molecules seem to be involved in local cytokine production by macrophages. However, the precise role of CD40 signaling in the pathogenesis of IBD is still poorly understood. The aim of the present study was to investigate the in vivo relevance of CD40 signaling in experimental colitis in SCID mice reconstituted with syngeneic CD45RBhighCD4+ T cells. The results demonstrated that CD40+ and CD40L+ cells as well as their mRNA levels were significantly increased in inflamed mucosa. Administration of anti-CD40L neutralizing mAb over an 8-wk period starting immediately after CD45RBhighCD4+ T cell reconstitution completely prevented symptoms of wasting disease. Intestinal mucosal inflammation was effectively prevented, as revealed by abrogated leukocyte infiltration and decreased CD54 expression and strongly diminished mRNA levels of the proinflammatory cytokines IFN-gamma, TNF, and IL-12. When colitic SCID mice were treated with anti-CD40L starting at 5 wk after T cell transfer up to 8 wk, this delayed treatment still led to significant clinical and histological improvement and down-regulated proinflammatory cytokine secretion. These data suggest that the CD40-CD40L interactions are essential for the Th1 inflammatory responses in the bowel in this experimental model of colitis. Blockade of CD40 signaling may be beneficial to human IBD.

Animals↗
PubMed2003

CD40, but not CD154, expression on B cells is necessary for optimal primary B cell responses.

CD40 is an important costimulatory molecule for B cells as well as dendritic cells, monocytes, and other APCs. The ligand for CD40, CD154, is expressed on activated T cells, NK cells, mast cells, basophils, and even activated B cells. Although both CD40(-/-) and CD154(-/-) mice have impaired ability to isotype switch, form germinal centers, make memory B cells, and produce Ab, it is not entirely clear whether these defects are intrinsic to B cells, to other APCs, or to T cells. Using bone marrow chimeric mice, we investigated whether CD40 or CD154 must be expressed on B cells for optimal B cell responses in vivo. We demonstrate that CD40 expression on B cells is required for the generation of germinal centers, isotype switching, and sustained Ab production, even when other APCs express CD40. In contrast, the expression of CD154 on B cells is not required for the generation of germinal centers, isotype switching, or sustained Ab production. In fact, B cell responses are completely normal when CD154 expression is limited exclusively to Ag-specific T cells. These results suggest that the interaction of CD154 expressed by activated CD4 T cells with CD40 expressed by B cells is the primary pathway necessary to achieve B cell activation and differentiation and that CD154 expression on B cells does not noticeably facilitate B cell activation and differentiation.

Animals↗
PubMed2004

Role of TNF receptor-associated factor 3 in the CD40 signaling by production of reactive oxygen species through association with p40phox, a cytosolic subunit of nicotinamide adenine dinucleotide phosphate oxidase.

To extend our previous report, which showed the production of the reactive oxygen species (ROS) after the CD40 ligation in the B cells, we further examined the possible mechanisms for ROS production and the involvement of CD40-induced ROS in p38 activation. Our research shows that the stimulation of WEHI 231 B lymphomas with anti-CD40 induced ROS production and p38 activation. An antioxidant N-acetyl-L-cysteine or an inhibitor for NADPH oxidase blocked both of these, but the inhibitors for 5-lipoxygenase did not. We also show that the treatment of cells with inhibitors for the phosphatidylinositol 3-kinase (PI3-K) interfered with the CD40-induced ROS production and p38 activation. In addition, when overexpressed with a dominant negative form of either Rac1 (N17Rac1) or the TNFR-associated factor (TRAF) 3, the WEHI 231 B cells did not show a full response to the CD40 stimulation to produce ROS. Molecular association studies further revealed that the TRAF3 association with p40(phox), a cytosolic subunit of NADPH oxidase and p85 (a subunit of PI3-K), may possibly be responsible for the production of ROS by CD40 stimulation in WEHI 231 B cells. Collectively, these data suggest that the CD40-induced ROS production by NADPH oxidase in WEHI 231 requires the role of TRAF3, as well as activities of PI3-K and Rac1.

Animals↗
PubMed2004

CD40 on adult human airway epithelial cells: expression and proinflammatory effects.

CD40/CD40 ligand interaction is an important pathway for B and T cell cooperation and function; functional CD40 molecules have recently been found on nonhematopoietic cells. We detected CD40 in vivo on normal human respiratory epithelial cells and showed that its expression is increased on inflamed airway epithelium. Subsequently, we analyzed its expression and function on primary cultures of human airway epithelial cells. Our data show that CD40 is up-regulated by IFN-beta and IFN-gamma, its ligation increases the surface expression of CD54 and CD106 and it may stimulate the release of IL-6 and IL-8. The use of Janus kinase 3 (JAK3) and NF-kappaB inhibitors suggests that both basal and CD40-induced release of the two cytokines is JAK3-dependent. Using colocalization techniques, we revealed the existence of CD40/JAK3 and CD40/TNFR-associated factor 2 interplay. The extent of these interactions may be partial (2-40% of the cells) or massive (80-90% of the cells) in cultured cells. Stimulation via CD40 causes a significant increase in the number of cells expressing colocalization only in the cultures displaying low frequency of initial colocalization. Thus, airway epithelial cells, activated by CD40, may behave as effector cells of the inflammation process and should be considered priority targets for anti-inflammatory therapy. This work identifies CD40 and the correlated JAK3 signaling molecule as potential molecular targets to block the inflammatory functions of epithelial cells.

Adult↗
PubMed2004

Cutting edge: long-lived CD8 memory and protective immunity in the absence of CD40 expression on CD8 T cells.

CD8 T cells need CD4 T cells to develop into long-lived, functional memory cells that provide protection against pathogen rechallenge. We investigated whether signaling via CD40 expressed on the CD8 cells themselves is involved in this cooperation. In murine responses to Listeria monocytogenes and lymphocytic choriomeningitis virus, we found no evidence of any requirement for CD40-CD40 ligand interaction at this level. No differences were observed between CD40(-/-) and CD40(+/+) CD8 T cells that had matured in the same environment when comparing their expansion in a primary or secondary response, their contribution to memory, and their ability to enter nonlymphoid tissues such as the liver. Thus, we find no evidence that CD40 ligand-expressing CD4 T cells are required to activate CD40 on CD8 T cells directly for the full differentiation of the cytotoxic T cell response.

Animals↗
PubMed2005

B cell receptor (BCR) cross-talk: CD40 engagement enhances BCR-induced ERK activation.

Bystander B cells may be initially stimulated through CD40, which enhances susceptibility to Fas-mediated apoptosis, before encountering Ag, which produces Fas resistance. A key issue in this process is to what extent CD40 cross-talk might affect subsequent BCR signaling. It has previously been shown that CD40 engagement bypasses or mitigates the need for Bruton's tyrosine kinase in subsequent BCR signaling for NF-kappaB activation. However, the full extent of the effects of CD40 on BCR signaling has not been delineated. In the present study we evaluated the possibility that CD40-mediated cross-talk also affects another principal outcome of BCR signaling: MAPK activation. We found that prior stimulation of primary murine B cells with CD40L markedly enhanced the level of ERK and JNK (but not p38 MAPK) phosphorylation produced by subsequently added anti-Ig Ab, and much, but not all, of this enhancement was independent of PI3K and phospholipase C. CD40L treatment similarly enhanced BCR-induced MAPK kinase (MEK) phosphorylation, and MEK was required for enhancement of ERK. Although BCR-induced c-Raf phosphorylation was also enhanced by prior CD40L treatment, c-Raf was not required for MEK/ERK phosphorylation. These results identify a novel system of receptor cross-talk between CD40 and BCR and indicate that the effects of CD40 engagement on subsequent BCR stimulation spread beyond NF-kappaB to involve the MAPK pathway.

Animals↗
PubMed1999

Differential responses to CD40 ligation among Burkitt lymphoma lines that are uniformly responsive to Epstein-Barr virus latent membrane protein 1.

Ligation of CD40 on the surface of B cells induces multiple phenotypic effects, many of which are mimicked by the EBV latent membrane protein 1 (LMP1) through its interaction with downstream components of the CD40 signaling pathway. Because the effects of LMP1 have been most closely studied in human Burkitt Lymphoma (BL) cell lines retaining a tumor biopsy-like phenotype in vitro, we have examined the response of a panel of such lines to CD40 ligation. Two distinct patterns of response were observed that were unrelated to the surface level of CD40 or to the EBV genome status of the lines. Following exposure to either CD40-specific mAbs or the soluble trimeric ligand (sCD40L), high responder (HR) lines showed rapid aggregation, activation of NF-kappa B, up-regulation of cell surface markers ICAM-1/CD54 and Fas/CD95, and growth inhibition. Aggregation was seen at lower doses than those required to elicit the other effects. By contrast, low responder (LR) lines showed no detectable response to CD40 mAbs, while their responses to sCD40L were limited to activation of NF-kappa B and up-regulation of CD95 only. However, in transfection experiments, LMP1 uniformly induced the full spectrum of phenotypic effects in both HR and LR lines. We conclude that some BL cell lines show a highly restricted response to CD40 ligation but remain fully susceptible to LMP1.

Burkitt Lymphoma↗
PubMed1999

Inhibition of human breast carcinoma growth by a soluble recombinant human CD40 ligand.

CD40 is present on B cells, monocytes, dendritic cells, and endothelial cells, as well as a variety of neoplastic cell types, including carcinomas. CD40 stimulation by an antibody has previously been demonstrated to induce activation-induced cell death in aggressive histology human B-cell lymphoma cell lines. Therefore, we wanted to assess the effects of a recombinant soluble human CD40 ligand (srhCD40L) on human breast carcinoma cell lines. Human breast carcinoma cell lines were examined for CD40 expression by flow cytometry. CD40 expression could be detected on several human breast cancer cell lines and this could be augmented with interferon-gamma. The cell lines were then incubated with a srhCD40L to assess effects on in vitro growth. srhCD40L significantly inhibited the proliferation of the CD40(+) human breast cancer cell lines. This inhibition could also be augmented with interferon-gamma. Viability was also affected and this was shown to be due to increased apoptosis of the cell lines in response to the ligand. Treatment of tumor-bearing mice was then performed to assess the in vivo efficacy of the ligand. Treatment of tumor-bearing SCID mice with the ligand resulted in significant increases in survival. Thus, CD40 stimulation by its ligand directly inhibits human breast carcinoma cells in vitro and in vivo. These results suggest that srhCD40L may be of clinical use to inhibit human breast carcinoma growth.

Animals↗
PubMed1999

Triggering of murine NK cells by CD40 and CD86 (B7-2).

NK cell-mediated cytotoxicity is regulated by both triggering and inhibitory signals. The interaction between MHC class I molecules expressed on target cells and specific MHC class I-binding receptors expressed by NK cells generally leads to inhibition of lysis. We have shown recently that CD80 (B7-1) in mice and CD40 in humans trigger NK cell-mediated cytotoxicity in vitro. In the present study, we show that murine CD40 and CD86 (B7-2) trigger murine NK cell-mediated cytotoxicity in vitro when expressed on tumor cells. Preincubation of the transfected cell lines with anti-CD40 F(ab')2 fragments or cytolytic T lymphocyte-associated Ag-4-Ig (CTLA-4-Ig) before the cytotoxic assay abolished the triggering effect. Furthermore, radiolabeled CD40- and B7-2-expressing cells were rapidly eliminated in vivo in an NK cell-dependent manner. NK cells from CD40 ligand (CD40L)-/- or CD28-/- mice were triggered by tumor cells transfected with CD40 and B7-2, respectively, and these transfectants were rapidly eliminated in vivo when inoculated into CD40L-/- and CD28-/- mice. This suggests that the CD40 and B7-2 molecules can interact with receptors on NK cells other than CD40L and CD28, respectively, and that these may account for some of the reactivities observed in the present study. Collectively, these data demonstrate that 1) costimulatory molecules, other than B7-1, can modulate NK cell responses in vitro, 2) they can also affect NK cell-dependent responses in vivo, and 3) parts of these reactions are independent of CD28 and CD40L.

Animals↗
PubMed1999

Surface membrane-expressed CD40 is present on tumor cells from squamous cell cancer of the head and neck in vitro and in vivo and regulates cell growth in tumor cell lines.

Because regional spread to lymph nodes without systemic spread is a relatively common event in squamous cell cancer of the head and neck (SCCHN), it is possible that lymphoid-related receptors or cytokines might directly impact the growth of these tumors. In the present study, we have shown by flow cytometry and Western blotting that the central lymphoid regulatory molecule, CD40, is expressed on the surface of all seven SCCHN tumor cell lines studied. Tumor cell lines also expressed epidermal growth factor (EGF) receptor, MHC class I, and CD95 (Fas) but did not uniformly express other important lymphoid regulatory molecules such as CD80, CD86, or interleukin (IL) 2 receptor components. CD40 ligation by trimeric CD40 ligand (CD40L) resulted in a 20-45% inhibition of tumor cell growth in three of seven cell lines tested. The cytokines IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-10, IL-11, and IL-15 neither inhibited nor stimulated growth in any of the cell lines tested. EGF had pleiotropic effects on cell growth; it inhibited growth in two cell lines, stimulated growth in one cell line, and had no effect in four cell lines. When coligation by EGF and CD40L was studied, additive or supra-additive growth inhibition was seen in four cell lines. Three cell lines were unaffected by EGF, CD40, or coligation with both reagents. Examination of tumor tissues from 12 previously untreated patients representing a broad spectrum of patients presenting with SCCHN demonstrated CD40 expression in all 12 tumor specimens. This study supports the notion that CD40 is a regulatory molecule for the growth of SCCHN. The important role of CD40-CD40L interactions in the regulation of immune cells in the lymph node and the unique high-level expression of CD40L by these immune cells lend support to the hypothesis that this ligand/receptor pair is an important mediator of cell growth in SCCHN.

Antibodies, Monoclonal↗
PubMed2000

Agonistic properties and in vivo antitumor activity of the anti-CD40 antibody SGN-14.

Ligation of CD40 is essential for primary B-cell activation and expansion and yet has suppressive or apoptotic effects on some CD40-expressing neoplasia. SGN-14 is a monoclonal antibody that binds to the human CD40 receptor. Here we report that SGN-14, in the presence of interleukin 4, provided a modest level of stimulation of peripheral blood B cells, as measured by proliferation. Stimulation was greatly enhanced in the presence of nonproliferating CD40 ligand-expressing cells. The enhanced agonistic activity could be attributed to a dose-dependent increase in CD40L binding to CD40 in the presence of SGN-14. In contrast to its proliferative effect on primary B cells, SGN-14 inhibited the growth of B-cell-derived tumor lines in vitro, and this growth inhibition was enhanced in the presence of CD40L-expressing cells. In vivo, SGN-14 showed significant antitumor activity in treating human B-cell lymphoma and multiple myeloma xenografted severe combined immunodeficient mice. Antitumor activity was not diminished by blunting murine natural killer activity, suggesting that CD40 ligation contributes to the antitumor efficacy of SGN-14. On the basis of these activities, SGN-14 is being pursued for therapeutic use in treating patients with CD40-expressing hematological malignancies.

Animals↗
PubMed2000

Role and expression of CD40 on human retinal pigment epithelial cells.

PURPOSE: To examine the CD40 costimulatory molecule expression on normal resting or activated adult human retinal pigment epithelium (hRPE) cells and to evaluate its role as an activation molecule considering the potential antigen presentation functions of hRPE cells. METHODS: Expression of HLA-DR and costimulatory (CD40, B7.1, B7.2, CD54, and CD58) molecules on hRPE cells was analyzed by flow cytometry. CD40 triggering was performed using soluble CD40L or cocultures with CD40L transfected fibroblasts. Interleukin (IL)-6, -8, -10, and -12 secretions were measured by enzyme-linked immunosorbent assay. Antigen presentation function of hRPE cells was assessed by coculturing hRPE cells with allogeneic T cells. T-cell proliferation was measured by [(3)H]-thymidine incorporation, and T-cell apoptosis by measurement of caspase-3 activity. RESULTS: Interferon (IFN)gamma-activated hRPE cells expressed CD40, but not B7.1 or B7.2. Although interferongamma enhanced IL-6 and IL-8 production, CD40 triggering of IFNgamma-activated hRPE cells did not induce IL-12 secretion. hRPE cells did not stimulate allogeneic resting T cells and downregulated phytohemagglutinin-activated allogeneic T cells via a cell-to-cell contact-dependent mechanism. Some induction of apoptosis was detected. CONCLUSIONS: CD40 is expressed on IFNgamma-activated hRPE cells. Its ligation leads to an increased production of IL-6 and IL-8 but fails to induce B7.1 or B7. 2 expression, or to induce IL-12 secretion. Accordingly, hRPE cells do not activate allogenic T cells but inhibit T-cell proliferation, partly through induction of apoptosis. These results suggest that hRPE cells could be implicated more in a deviant antigen presentation. If the exact molecular mechanisms are unclear, it is likely that CD40-CD40L interaction could play a role in this process.

Animals↗
PubMed2001

CD40 cross-linking bypasses the absolute requirement for CD4 T cells during immunization with melanoma antigen gene-modified dendritic cells.

Genetic immunization of mice with dendritic cells (DCs) engineered to express a melanoma antigen generates antigen-specific, MHC-restricted, CD4-dependent protective immune responses. We wanted to determine the role of CD4 cells and CD40 ligation of MART-1 gene-modified DC in an animal model of immunotherapy for murine melanoma. CD4 knock-out (CD4KO) or antibody-depleted mice were immunized with DC adenovirally transduced with the MART-1 gene (AdVMART1/DC) with or without CD40 cross-linking. Tumor protection was absent in CD4-depleted mice, but protection was reestablished when the CD40 receptor was engaged using three different constructs. Transduction of DCs with vectors expressing the Th1 cytokines interleukin (IL)-2, IL-7, or IL-12 could not reproduce the CD40-mediated maturation signal in this model. CD8 T-cell depletion in CD4KO mice immunized with CD40-ligated DCs abrogated the protective response. Pooled analysis of CD40 cross-linking of AdVMART1/DC administered to wild-type C57BL/6 mice revealed an overall enhancement of antitumor immunity. However, this effect was inconsistent between replicate studies. In conclusion, maturation of AdVMART1-transduced DCs through the CD40 ligation pathway can promote a protective CD8 T-cell-mediated immunity that is independent of CD4 T-cell help.

Adenoviridae↗
PubMed2002

Disruption of CD40/CD40 ligand interaction with cleavage of CD40 on human gingival fibroblasts by human leukocyte elastase resulting in down-regulation of chemokine production.

CD40 is a crucial element in the process of fibroblast activation. We demonstrated that treatment of human gingival fibroblast (HGF) with human leukocyte elastase (HLE), a neutrophil serine protease, down-regulated the expression of CD40 and binding to the CD40 ligand (CD40L) using flow cytometry. The other neutrophil serine proteases, cathepsin G and proteinase 3, exhibited markedly less activity for CD40 reduction. The CD40 reduction by HLE was also observed in skin and lung fibroblasts, but not in monocytes, macrophages, and dendritic cells. The reduction resulted from direct proteolysis by HLE on the cell surface, because HLE reduced CD40 on fixed HGF and also on cell lysates and membranes. HLE treatment of HGF decreases interleukin (IL)-8 and macrophage chemoattractant protein-1 production by HGF when stimulated by CD40L, but not by IL-1alpha, suggesting that HLE inhibited a CD40-dependent cell activation. These results suggest that HLE possesses an anti-inflammatory effect for the HGF-mediated inflammatory process.

Adolescent↗