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PubMed1985

Surface membrane expression by human blood leukocytes and platelets of decay-accelerating factor, a regulatory protein of the complement system.

The decay-accelerating factor (DAF), an integral membrane protein of approximately 75,000 mol wt that regulates the stability of the C3 convertases of the classical and alternative complement pathways, was initially isolated from normal erythrocyte stroma and used to prepare a polyclonal antiserum. Previously, anti-DAF antiserum has been used to immunoprecipitate DAF from surface-labeled normal erythrocytes and to document the deficiency of DAF on the surface of erythrocytes from patients with paroxysmal nocturnal hemoglobinuria, a condition in which erythrocytes express abnormal sensitivity to complement-mediated lysis. DAF has now been demonstrated by cytofluorography with anti-DAF F(ab')2 and fluoresceinated second antibody to be present on the surface of resting polymorphonuclear leukocytes (PMN), monocytes, lymphocytes, and platelets. Populations of PMN, monocytes, and platelets each exhibited a unimodal distribution of fluorescent staining, reflecting uniform cellular expression of DAF antigen, while the lymphocyte population had a skewed pattern of staining, indicating the heterogeneous expression of DAF antigen. For platelets, the shift in mean fluorescence channel observed with cytofluorographic analysis was minimal, but the presence of surface DAF on platelets was demonstrated by specific and saturable anti-DAF F(ab')2 binding. The DAF antigen, analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of dithiothreitol-reduced anti-DAF immunoprecipitates prepared from surface-labeled, isolated populations of cells, presented a single polypeptide chain of approximately 84,000 mol wt for PMN and 75,000 to 80,000 mol wt for monocytes, T and B lymphocytes, and platelets. Thus, the complement regulatory protein, DAF, is expressed on the surface of all major types of circulating blood cells from normal donors.

Blood Platelets↗

PubMed1998

Uptake of lithium carmine by sinusoidal endothelial and Kupffer cells of the rat liver: new insights into the classical vital staining and the reticulo-endothelial system.

Sinusoidal cells in the rat liver were studied in vivo and in vitro using the original vital staining with lithium carmine, which has contributed much to the development of the concept of the reticulo-endothelial system. Immunohistochemical and electron-microscopic studies revealed that the dye-incorporating cells were sinusoidal endothelial cells, Kupffer cells, and monocytes. The endothelial cells took up much more dye than did the Kupffer cells and bulged largely into the sinusoidal lumen. Electron microscopy revealed that small particles of lithium carmine were associated with coated vesicles of endothelial cells and ruffled membranes of Kupffer cells. In the endothelial cells, these particles were present in various concentrations within vacuolated structures and condensed in the lysosomes forming large aggregates of lithium carmine lumps. These lumps showed crystalline structures, within which the size of the individual particle was up to 30 nm in width and 50 nm in length. A few endothelial cells containing abundant dye underwent degeneration, and some were taken up by Kupffer cells. Liver endothelial cells isolated from lithium carmine-administered rats endocytosed fluorescence-labeled collagen. Isolated endothelial cells from normal rat liver, when cultured with lithium carmine, did not take up any dye, and their endocytosis of formaldehyde-treated albumin was inhibited dose-dependently. We conclude that in the liver, endothelial cells, but not Kupffer cells, predominantly take up lithium carmine. Furthermore, we propose the existence of a generalized cell system based on its vital staining capacity.

Animals↗

PubMed2005

The JAK2V617F tyrosine kinase mutation in myeloproliferative disorders: status report and immediate implications for disease classification and diagnosis.

Janus kinase 2 (JAK2) is a cytoplasmic protein-tyrosine kinase that catalyzes the transfer of the gamma-phosphate group of adenosine triphosphate to the hydroxyl groups of specific tyrosine residues in signal transduction molecules. JAK2 mediates signaling downstream of cytokine receptors after ligand-induced autophosphorylation of both receptor and enzyme. The main downstream effectors of JAK2 are a family of transcription factors known as signal transducers and activators of transcription (STAT) proteins. The myeloproliferative disorders (MPD), a subgroup of myeloid malignancies, are clonal stem cell diseases characterized by an expansion of morphologically mature granulocyte, erythroid, megakaryocyte, or monocyte lineage cells. Among the traditionally classified MPD, the disease-causing mutation has been delineated, thus far, for only chronic myeloid leukemia (ie, bcr/abl). In the past 3 months, 7 different studies have Independently described a close association between an activating JAK2 mutation (JAK2V617F) and the classic bcr/abi-negative MPD (ie, polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia) as well as the less frequent occurrence of the same mutation in both atypical MPD and the myelodysplastic syndrome. The particular finding is consistent with previous observations that have implicated the JAK/STAT signal transduction pathway in the pathogenesis of bcr/abl-negative MPD, Including the phenotype of growth factor independence and/or hypersensitivity. The current article summarizes this new information and discusses its implications for both classification and diagnosis of MPD.

Algorithms↗

PubMedDate not supplied

Adult chronic granulomatosis disease-like neutrophil granulocyte disorder corrected by dialysable leukocyte extract.

A 47 year old female presented with a septic clinical picture including fever, abscesses, late cachexia, and unmanageable by disease. Similar characteristics to chronic granulomatosis disease (CGD) seriously decreased intracellular killing activity and chemiluminescence, granulomas in the histology, and the role of genetic factors were found, suggesting that our case is CGD-like disorder, manifested in an adult. Dialysable leukocyte extract (DLE) therapy, complemented with fresh normal plasma, resulted in a striking clinical improvement and there was an increase in the in vitro PMNL intracellular killing activity, too. Although it is generally accepted that DLE derives from monocytes and lymphocytes, it is possible that DLE is a family of DNA-oligopeptide molecules, including factors derived from PMNLs which are capable of influencing PMNL function, transferring information from normal cells. Our results also suggest that it would be worth trying DLE in patients with classic CGD.

Abscess↗

PubMed1997

Four conserved promoter motifs regulate transcription of the gene encoding human complement component C2.

The early complement components of the classical activation pathway of the complement cascade include the components C1, C4, C2, and C3. These components act in concert to opsonize bacteria, clear immune complexes, and produce inflammatory mediators. They are not structurally homologous nor are they coordinately regulated. The expression of the early complement components is divergent in terms of cytokine responsiveness and tissue specificity. The only pattern of expression shared by the early complement components is inducibility by gamma-IFN and expression in cells of hepatic or monocytic lineage. Nevertheless, four novel conserved promoter motifs were identified in the 5' flanking region of multiple early complement component promoters. Mutation of these four motifs in the C2 promoter decreased transcription in hepatoma cells in transient transfection analyses, and a synthetic promoter consisting of just the four motifs supported transcription in hepatoma cells. Electrophoretic mobility shift assays demonstrate that three of the four conserved elements bind DNA-binding proteins in a tissue-specific manner. One DNA-binding protein is expressed ubiquitously, but the other three are restricted to cells of monocytic or hepatic lineage. Two of the DNA-binding proteins appear to be members of the zinc-finger family of transcription factors. Therefore, these four motifs appear to bind DNA-binding proteins that may function in the tissue-specific expression of C2. Conservation of these four motifs in multiple early complement component genes suggests that these may represent a conserved transcriptional strategy.

Carcinoma, Hepatocellular↗

PubMed2001

Nonphlogistic clearance of late apoptotic neutrophils by macrophages: efficient phagocytosis independent of beta 2 integrins.

Neutrophils undergo constitutive death by apoptosis, leading to safe nonphlogistic phagocytosis and clearance by macrophages. Recent work has shown that before secondary necrosis, neutrophils exhibiting classical features of apoptosis can progress to a morphologically defined late apoptotic state. However, whether such neutrophils could be safely cleared was unknown. We now report that human late apoptotic neutrophils could be purified from cultured neutrophil populations undergoing constitutive death and were subsequently ingested by human monocyte-derived macrophages by serum-independent mechanisms that did not trigger the release of IL-8 or TNF-alpha. Such ingestion was specifically inhibited by Abs to thrombospondin-1 and the alpha(v)beta(3) vitronectin receptor. Murine bone marrow-derived macrophage phagocytosis of late and early apoptotic neutrophils occurred by similar mechanisms, proceeding with the same efficiency as that observed for wild-type controls when macrophages from [alpha(m)](-/-) or [beta(2)](-/-) mice were used. We conclude that specific nonphlogistic, beta(2) integrin-independent mechanisms involving thrombospondin-1 and alpha(v)beta(3) allow macrophages to ingest late apoptotic neutrophils without eliciting inflammatory cytokine secretion.

Animals↗

PubMed2006

[The influence of diabetes mellitus and insulin resistance on receptor CD36 expression. Part II. The role of receptor CD36 in the pathomechanism of diabetes complications].

Glucose metabolism disorders are significant risk factors for accelerated atherosclerosis, but the exact pathogenesis of this impact and possible co-factors are not precisely known. On the other hand, only two thirds of all atherosclerosis cases are linked to so-called "classic" risk factors, and numerous studies are conducted to recognize those non-classic risk factors, among which homocysteine and adhesive molecules are the most often mentioned. Recently, the class B scavenger receptor CD36 has become an object of interest. Receptor CD36 is a membrane glycoprotein found on the surface of many cells, such as endothelial cells, cardiomyocytes, dendritic cells, platelets, monocytes, and macrophages. Ligands for receptor CD36 are oxidized LDL particles, long-chain fatty acids, collagens, thrombospondin I, apoptotic cells, and phospholipids. Receptor CD36 plays an important role in various processes, e.g. inner immune system response, apoptotic and necrotic cells removal, transport of fatty acids, and inhibition of neoplastic angiogenesis. Scavenging oxidized LDL particles is one of its most important functions. The most recent studies put forward the participation of receptor CD36 in atherogenesis. Additionally, increased CD36 expression has been described in diabetes mellitus and insulin resistance and in the pathogenesis of diabetic macro- and microangiopathy. Confounding data regarding human hereditary receptor CD36 deficiency as well as still unknown interactions between antidiabetic drugs and CD36 expression suggest the necessity for further studies on the participation of receptor CD36 in the atherogenesis linked with glucometabolic disorders and in the development of diabetes mellitus complications.

Animals↗

PubMed1994

Rapid desensitization of the histamine H2 receptor on the human monocytic cell line U937.

In the present study we have subjected the histamine H2 receptor on the monocytic cell line U937 to a thorough pharmacological characterization using a series of selective histamine H1, H2 and H3 receptor agonists and antagonists. Recent reports have demonstrated the existence of a histamine H2 receptor on HL-60 and HGT-1 cells with a pharmacological profile distinct from the commonly described histamine H2 receptor. U937 cells, however, seem to express classical histamine H2 receptors. Histamine and dimaprit dose dependently induce the formation of cAMP, whereas dimaprit's inactive analogues, nordimaprit and homodimaprit, show reduced potencies. Histamine H1 and H3 receptor agonists do not show histamine H2 receptor activity. Various histamine H2 receptor antagonists are able to block the histamine induced production of cAMP with an antagonistic profile comparable to that observed in the guinea-pig right atrium. Furthermore, endogenous histamine H2 receptors in U937 cells are found to be susceptible to receptor desensitization, a mechanism which may become apparent under pathophysiological conditions or during drug therapy. A 30-min pre-exposure of U937 cells to histamine (100 microM) results in a 50% attenuation of the production of cAMP to a subsequent application of an agonist. Desensitization of the histamine H2 receptor in U937 cells is found to be homologous as the beta-adrenoceptor mediated response remained unaffected.

Cells, Cultured↗

PubMed1986

Rapid killing of actinomycin D-treated tumor cells by mononuclear phagocytes: characterization of effector cells in mice.

Pretreatment with Actinomycin D (Act D, 1 microgram/ml for 3 hr) rendered WEHI 164 tumor cells susceptible to killing by mouse resident or peptone-induced peritoneal exudate cells (PEC) in a 6-hr 51Cr release assay. Cytotoxicity was attributed to cells of the monocyte macrophage lineage on the basis of tissue distribution, separation by adherence on plastic and carbonyl iron, membrane antigens, and expression in mice with defective T cell- or NK cell-mediated immunity. Macrophages from four strains of mice (C3H/HeJ, A/J, P/J, C57B1/10 ScCR) previously shown to have defective "classical" nonspecific tumoricidal activity were examined for killing of Act-D-treated WEHI 164 cells. C3H/HeJ peritoneal macrophages had little or no DDCC, whereas cells from A/J, P/J, and C57B1/10 ScCR mice had normal levels of this reactivity. Tumor cells exposed to ActD were heterogenous in their susceptibility to killing by PEC, with five lines showing significant, though variable, lysis, whereas 12 tumor lines, normal fibroblasts, and lymphoblasts were not appreciably killed under the same conditions. Macrophage-mediated DDCC was also detectable in a colony assay. DDCC could explain how macrophages contribute to the antitumor activity of selected chemotherapeutic agents in murine tumor models.

Animals↗

PubMed1995

Mannose binding protein (MBP) enhances mononuclear phagocyte function via a receptor that contains the 126,000 M(r) component of the C1q receptor.

Mannose-binding protein (MBP), C1q, the recognition component of the classical complement pathway, and pulmonary surfactant protein A (SP-A) are members of a family of molecules containing a collagen-like sequence contiguous with a noncollagen-like sequence, and usually having the properties of a lectin. C1q and SP-A have been shown to enhance monocyte FcR- and CR1-mediated phagocytosis, suggesting that the common structural features of the collagen-like domains may provide a basis for this immunologically important function. Results presented here demonstrate that MBP also enhanced FcR-mediated phagocytosis by both monocytes and macrophages, and stimulated CR1-mediated phagocytosis in human culture-derived macrophages and in phorbol ester-activated monocytes. Furthermore, a monoclonal antibody that recognizes a 126,000 M(r) cell surface protein and inhibits C1q-enhanced phagocytosis, inhibited the MBP-mediated enhancement of phagocytosis. Thus, the receptors that mediate the enhancement of phagocytosis by MBP and C1q share at least one critical functional component, the 126,000 M(r) ClqRP.

Carrier Proteins↗

PubMed2003

Tuberculous pleural effusions.

Tuberculosis is the most frequent cause of death due to infectious diseases. In Europe, it is one of the most frequent types of pleural effusions in young patients. Tuberculosis is caused by the rupture of a pulmonary subpleural caseous focus, which releases mycobacterium into the pleural cavity, thereby triggering an immune response involving mainly macrophages, CD4+ T lymphocytes, and the cytokines released by these cells (especially interleukin 1, interleukin 2, and ?-interferon). In recent years, classical microbiological and histological methods of diagnosis have been joined by biochemical analyses of pleural fluid, which are faster and can be more sensitive. In particular, tuberculous effusions have high adenosine deaminase (ADA) activity, apparently due to high levels of the ADA isoenzyme ADA2, which is only found in monocytes and macrophages (although certain data suggest the possible involvement of activated T cells, too). It has been recommended that treatment for tuberculosis be initiated if analysis of pleural fluid shows high ADA activity, a lymphocyte/neutrophil ratio greater than 0.75, and no malignant cells. Another highly efficient marker is ?-interferon, which is released by activated CD4+ T cells, but its high price is an obstacle to its routine determination in clinical practice. Identification of mycobacterial DNA by means of the polymerase chain reaction (PCR) is less efficient, apparently because its sensitivity depends heavily on mycobacterium concentration. No other biochemical parameters currently appear to be of marked relevance for the diagnosis of tuberculous pleural effusion (TPE). TPE responds well to the standard treatment for tuberculosis. However, 50% of TPE patients have a thickened pleura as a result of the accumulation of fluid, and in 16% the quantity of effusion increases during treatment, even if corticosteroids are administered. It therefore seems reasonable for treatment with antituberculous drugs to be preceded by therapeutic thoracocentesis to remove as much fluid as possible.

Journal Article↗

PubMed2000

Mediators of hypersensitivity pneumonitis.

Inhalation of Saccharopolyspora rectivirgula (S. rectivirgula) causes farmer's lung disease, a classic example of hypersensitivity pneumonitis (HP). HP is characterized by bronchoalveolar lavage fluid (BALF) neutrophilia (within the first 48 hours after inhalation), followed by BALF lymphocytosis. We utilized a well-described murine model of HP to determine the timing of the appearance of the C-C chemokines monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1alpha (MIP-1alpha); the inflammatory cytokines tumor necrosis factor (TNF), interleukin-1alpha (IL-1alpha), and interleukin-6 (IL-6); and the Th1 -differentiating cytokine interleukin-12 (IL-12) in BALF. After a single intratracheal administration of S. rectivirgula, there was remarkable BALF neutrophilia (peak 24 to 48 hours), followed by a BALF lymphocytosis (peak 48 to 72 hours) in both C57Bl/6 and BALB/c mice that was preceded by the appearance of MIP-1alpha in BALF (peak 4 to 6 hours) and MCP-1 (peak at 48 hours). In both strains of mice there was a striking increase of BALF IL-12 (peak 48 to 72 hours). There was also an increase in BALF IL-6, IL-1alpha, and TNF that was greater in the BALB/c mice than in the C57Bl/6 mice. S. rectivirgula induced the secretion of MIP-1alpha, MCP-1, IL-6, IL-1alpha, and IL-12 from the murine macrophage cell line J774A.1; MIP-1alpha, IL-6, IL-1alpha, IL-12, and TNF from C57Bl/6 alveolar macrophages; and IL-1alpha, IL-6, and TNF-but not IL-12-from BALB/c alveolar macrophages. We conclude that chemokines and cytokines induced by intratracheal administration of S. rectivirgula precede BALF neutrophilia and lymphocytosis and may cause differentiation of Th1 cells; we also conclude that pulmonary macrophages represent a potential source of these substances.

Alveolitis, Extrinsic Allergic↗

PubMed2006

Long pentraxin 3: a marker of inflammation in untreated psoriatic patients.

Psoriasis is a common cutaneous disorder characterized by abnormal epidermal differentiation, proliferation and inflammation mediated by dermal infiltrates, such as T cells, neutrophils, dendritic cells and macrophages. There are renewed interest in the role of components of the innate immune system. Cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6, and -1beta involved in pathogenic phenomena in psoriasis are known as inducers of the acute phase response. Among the large group of acute phase reactants, C-reactive protein (CRP) and fibrinogen are of special interest in psoriasis. The PTX-3, a long pentraxin sharing similarities with the classical short proteins. Thus, considering the numerous biological roles of inflammatory cytokines and their relationship with inflammatory markers, such as CRP and fibrinogen we have investigated the role of PTX3 in psoriasis. To this aim PTX3, TNF-alpha, IL-6 and IL-1beta in plasma and in monocytic cultures by enzyme linked immunosorbent assay (ELISA) in 44 patients including severe and mild psoriasis were measured. An increased production of PTX3, both in supernatant of purified monocytes and in plasma from patients with severe psoriasis, was found. The significant correlation, between cellular production and plasma levels of PTX3 in psoriasis was found as a sign of cellular activation by monocytes/macrophages that first infiltrate the psoriatic lesion. In severe psoriasis, a significant correlation between psoriasis area and severity index (PASI) score and TNF-alpha and IL-6 levels in both supernatant of monocytes and plasma was found. In contrast, no correlation was found for IL-1beta. By immunohistochemistry and immunofluorescence, a strong PTX3 staining in fibroblasts, endothelial cells and monocytes/macrophages in severe psoriatic lesional skin was detected. Finally, a positive correlation between PTX3 and disease activity of psoriasis was observed as PASI score was elevated. These findings suggest that PTX3 could be used as a further marker of disease activity of psoriasis.

Adult↗

PubMed1979

Immune mechanisms against canine distemper. I. Identification of K cell against canine distemper virus infected target cells in vitro.

Canine peripheral blood lymphocytes, polymorphonuclear leucocytes (PMN) and monocytes (macrophages) were obtained by various cell separation techniques and were tested for their cytotoxic capacity against antibody-sensitized canine distemper virus (CDV) infected Vero cells by an in vitro chromium release assay. Canine lymphocytes were found to destroy CDV infected target cells effectively, while neither PMN nor monocytes (macrophages) could do so. The active lymphocyte was characterized by various rosetting techniques to be a non-T and a non-B lymphocyte. These cells bear no surface immunoglobulin (SIg-) but possessed both Fc receptors (Fc+) and complement receptors (EAC+) suggesting that these cells are neither classical T nor B cells. The possible roles of this K cell in the resistance against canine distemper are discussed.

Animals↗

PubMed2006

Interleukin (IL)-19, IL-20 and IL-24 are produced by and act on keratinocytes and are distinct from classical ILs.

Due to their structural similarity, interleukin (IL)-19, IL-20, IL-22, IL-24 and IL-26 were combined with IL-10 in the so-called IL-10 family. To expand the knowledge on IL-19, IL-20 and IL-24, we systematically and quantitatively analysed the expression of these mediators and their receptor chains in vitro and in vivo under various conditions and in comparison with other IL-10 family members. In vitro, IL-19, IL-20 and IL-24 were produced not only by activated immune cells, particularly monocytes, but also to a similar extent by keratinocytes. IL-1beta increased the expression of these mediators 1000-fold (IL-19) and 10-fold (IL-20 and IL-24) in keratinocytes. In vivo, these cytokines were expressed preferentially in inflamed tissues. The absence of either R1 chain for the two types of receptor complexes for these cytokines (IL-20R1/IL-20R2 and IL-22R1/IL-20R2) on immune cells implies that they cannot act on these cells. In fact, IL-19, IL-20 and IL-24 did not induce activation of signal transducer and activator of transcription (STAT) molecules in immune cells. Instead, several tissues, particularly the skin, tissues from the reproductive and respiratory systems, and various glands appeared to be the main targets of these mediators. Keratinocytes expressed both receptor complexes; however, the expression of IL-22R1 was 10 times higher than that of IL-20R1. Interferon-gamma further increased the expression of IL-22R1 and decreased that of IL-20R1, suggesting that under T1 cytokine conditions these mediators primarily affect keratinocytes via the IL-22R1/IL-20R2 complex. In summary, these data support the notion that IL-19, IL-20 and IL-24 are distinct from classical ILs and constitute a separate subfamily of mediators within the IL-10 family.

Animals↗

PubMed2003

A histopathologic, immunohistochemical, and ultrastructural study of the intestine in pigs inoculated with classical swine fever virus.

The aim of this study was to report on the lesions occurring in the intestine during experimental classical swine fever (CSF) and to clarify the nature of infected cells and the distribution of viral antigen. Thirty-two pigs were inoculated with the virulent CSF virus (CSFV) isolate Alfort 187 and slaughtered from 2 to 15 postinoculation days; four animals of similar background served as a control group. Immunohistochemistry, electron microscopy, and the transferase-mediated deoxyuridine triphosphate nick-end labeling method were used to detect viral antigens and apoptosis. The results showed progressive lymphoid depletion and mucosal necrosis. The lymphoid depletion could have been caused by apoptosis of lymphocytes but could not be directly attributed to the effect of CSFV on these cells. Vascular changes, pathogenic bacteria, and viral infection of epithelial cells were ruled out as causes of necrotic lesions. However, large virally infected monocytes-macrophages with ultrastructural changes indicative of activation were observed in the intestine. This suggests that monocytes-macrophages play an important role in the pathogenesis of intestinal lesions. An understanding of the function of these cells will require additional study.

Animals↗

PubMed1980

Receptors on guinea-pig erythrocytes specific for cell-bound fourth component of human complement (C4).

Guinea-pig erythrocytes have receptors for heterologous (human and rabbit) complement activated by the classical pathway on cell surfaces. This was shown in the present study by rosette-forming reactions of guinea-pig erythrocytes and human lymphocytes or sheep erythrocytes pre-treated with antibody and human R3 complement. The binding is temperature-dependent and is enhanced by treating the guinea-pig erythrocytes with neuraminidase. The receptors were shown to be specific for C4 by inhibition tests employing a range of anti-human complement antibodies (including anti-Clq, -Cl inhibitor, -C4, -C2, -C3 and -C3b inactivator). Of these reagents, only anti-C4 inhibited the receptor activity, indicating that the guinea-pig erythrocyte C4-receptors differ from those on lymphocytes, monocytes, polymorphonuclear leucocytes and human erythrocytes which are reported to react with both C3b and C4b. In contrast to the strong affinity observed for heterologous C4, guinea-pig erythrocytes appear to react very weakly, if at all, with homologous C4.

Animals↗

PubMed2005

Triptolide affects the differentiation, maturation and function of human dendritic cells.

Triptolide is a purified component from a traditional Chinese herb Tripterygium wilfordii Hook F. It has been shown to have anti-inflammatory and immunosuppressive activities by its inhibitory effect on T cells. But the effect of triptolide on dendritic cells (DC) is unknown. Dexamethasone (Dex) is a classic immunosuppressive agent known to suppress the immune response at different levels and has recently found to modulate the development of DC, thereby influencing the initiation of the immune response. In this study, we investigated the affect of triptolide on the differentiation, maturation and function of DC differentiated from human monocytes (MoDC) in vitro in the presence of GM-CSF and IL-4. Dex was included in the study as a reference. Our data show that both triptolide and Dex prevented the differentiation in immature MoDC by inhibiting CD1a, CD40, CD80, CD86 and HLA-DR expression but upregulating CD14 expression, as well as by reducing the capacity of MoDC to stimulate lymphocyte proliferation in the allogeneic mixed lymphocyte reaction. They blocked the maturation of MoDC as totally blocked induction of CD83 expression and absent upregulation of CD40, CD80, CD86 and HLA-DR. In addition, higher concentration of triptolide (20 ng/ml) and 10(-6) M Dex induced apoptosis in MoDC as measured by expression of APO2*7 and DNA fragmentation (TUNEL assay). However, the phagocytic capacity of MoDC was enhanced by triptolide but not Dex. Therefore, the suppression of DC differentiation, the function in immature DCs as well as the inhibition of DC maturation by triptolide may explain some of its immunosuppressive properties. It is suggested that DCs are a primary target of the immunosuppressive activity of triptolide.

Antigens, CD↗