RESUMO
Fish consumers may develop allergic reactions following the ingestion of fish products containing nematode larvae within the genus Anisakis. Sensitized patients may cross-react with proteins from insects, mites and mollusks, leading to allergic reactions even in the absence of the offending food. Potential cross-reactivity in Anisakis-allergic patients with larval proteins from other zoonotic parasites present in freshwater and sea fish should be investigated due to an increasing occurrence in certain fish stocks, particularly Contracaecum osculatum. In this work, we evaluated IgE-cross reactions by in vivo (skin prick tests with parasites extracts) and in vitro methods (IgE-ELISA and IgE-immunoblot). In vivo skin prick tests (SPT) proved the reactivity of Anisakis-sensitized patients when exposed to C. osculatum antigens. Sera from Anisakis-sensitized patients confirmed the reaction with somatic antigens (SA) and excretory/secretory proteins (ES) from C. osculatum. Only anecdotal responses were obtained from other freshwater worm parasites. Consequently, it is suggested that Anisakis-sensitized humans, especially patients with high levels of specific anti-Anisakis antibodies, may react to C. osculatum proteins, possibly due to IgE-mediated cross-reactivity.
RESUMO
To understand factors that regulate leukocyte entry and positioning within human melanoma tissues, we performed a multiparametric quantitative analysis of two separated regions: the intratumoral area and the peritumoral stroma. Using two mesenchymal markers, fibroblast activation protein (FAP) and CD90, we identified three subsets of mesenchymal cells (MCs): (i) intratumoral FAP(+)CD90(low/-) MC, (ii) peritumoral FAP(+)CD90(+) MC, and (iii) FAP(-)CD90(+) perivascular MC. We characterized CD90(+) MCs, which showed a stable CCL2-secretory phenotype when long-term expanded ex vivo, and heavily surrounded peritumoral Duffy antigen receptor for chemokine(+) (DARC) postcapillary venules, supporting a role for these vessels in peritumoral inflammatory leukocyte recruitment. Conversely, the intratumoral area was variably invaded by FAP(+)CD90(low/-) MCs that colocalized with a distinct extracellular matrix (ECM) network. A positive correlation was observed between intratumoral stromal cell/ECM networks and leukocyte infiltration among tumor cells (TCs), as well as in a stroma-dependent xenograft tumor model. Adoptively transferred T lymphocytes preferentially infiltrated tumors composed of TC+MC, compared with TCs only. Altogether, our results suggest that a variety of MCs contribute to regulate different steps of leukocyte tumor infiltration, that is, CD90(+) cells surrounding peritumoral vessels secrete CCL2 to recruit CCR2(+) leukocytes at the tumor periphery, whereas intratumoral FAP(+) cells organize a stromal scaffold that contact guide further invasion among densely packed tumor cells.
Assuntos
Leucócitos/patologia , Melanoma/secundário , Neoplasias Cutâneas/patologia , Microambiente Tumoral/imunologia , Animais , Biópsia , Comunicação Celular/imunologia , Movimento Celular/imunologia , Quimiocina CCL2/imunologia , Humanos , Leucócitos/imunologia , Melanoma/irrigação sanguínea , Melanoma/imunologia , Mesoderma/imunologia , Mesoderma/patologia , Camundongos , Camundongos Endogâmicos BALB C , Invasividade Neoplásica , Transplante de Neoplasias , Receptores CCR2/imunologia , Neoplasias Cutâneas/irrigação sanguínea , Neoplasias Cutâneas/imunologia , Células Estromais/imunologia , Células Estromais/patologiaRESUMO
BACKGROUND: Pollutants and other stressing factors like mold infection might increase the production of pathogen-related proteins in plants. Since this is invoked as one of the causes for the high prevalence of allergic diseases in developed countries, we aimed to determine the potential effect of environmental pollution, with or without mold infection of the trees, on the allergenic potency of pine pollen (Pinus radiata). METHODS: Pine pollen samples were recovered from three selected areas: low polluted (A), highly polluted (B) and highly polluted and infected with fungi (Spheropsis sapinea) (C). The allergenic potency of pollen from areas A, B or C were compared in vivo in 35 pine pollen-allergic patients by skin prick test and specific IgE (sIgE) quantification. Pollen was also analyzed in vitro by SDS-PAGE immunoblotting, RAST inhibition and cDNA-AFLP (amplified fragment length polymorphism) to compare differences in proteins and mRNA expression. RESULTS: The allergenic potency measured by prick test, sIgE and RAST inhibition was greater in pollen A, which was exposed to smaller amounts of NO(x), PM(10) and SO(2) but greater amounts of O(3). No differences were found in IgE-binding bands in immunoblotting or densitometry of the bands. In cDNA-AFLP, three homologous transcript-derived fragments were expressed in samples B only, with an expressed sequence tag related with stress-regulated gene expression. CONCLUSIONS: A greater allergenic potency, in terms of skin tests and sIgE, is observed in pine pollen coming from unpolluted areas. We consider that this fact might be related to a higher exposure to ozone, resulting in a greater expression of allergenic proteins.
Assuntos
Poluição Ambiental , Fungos/imunologia , Pinus/imunologia , Pinus/microbiologia , Pólen/imunologia , Rinite Alérgica Sazonal/epidemiologia , Feminino , Regulação da Expressão Gênica de Plantas , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/imunologia , Proteínas de Choque Térmico/metabolismo , Humanos , Imunoglobulina E/metabolismo , Masculino , Pessoa de Meia-Idade , Compostos de Nitrogênio/efeitos adversos , Ozônio/efeitos adversos , Proteínas de Plantas/genética , Proteínas de Plantas/imunologia , Proteínas de Plantas/metabolismo , Ligação Proteica , Rinite Alérgica Sazonal/complicações , Rinite Alérgica Sazonal/imunologiaRESUMO
Tumor cell migration involved in metastases is a tightly regulated, nonrandom process. Chemokines have been identified as critical molecules guiding cell migration. We performed a prospective study to analyze a possible association between the expression of chemokine receptors CXCR3 and CXCR4 by primary melanoma and clinical outcome. Forty primary melanomas were available for analysis; 57% of the tumors expressed CXCR3 and 35% expressed CXCR4 by melanoma cells. At initial diagnosis, 5 patients had subclinical lymph node involvement and after a median follow-up time of 32 months, 2 additional patients developed regional lymph node metastases and 5 patients developed distant metastases. The expression of CXCR4, but not CXCR3, by melanoma cells in primary lesions was significantly associated with the presence of ulceration, increased tumor thickness, a greater risk of developing regional and distant metastases and a higher mortality rate. Our study underscores the value of CXCR4 expression as a useful marker for predicting outcome in patients with localized melanoma. In addition, our findings support that, among chemokine receptors, CXCR4 might be an appropriate therapeutic target for adjuvant therapy in patients at risk for metastatic disease.
Assuntos
Melanoma/metabolismo , Receptores CXCR4/metabolismo , Receptores de Quimiocinas/metabolismo , Neoplasias Cutâneas/metabolismo , Humanos , Imuno-Histoquímica , Receptores CXCR3RESUMO
Zymosan is a beta-glucan, mannan-rich yeast particle widely used to activate the inflammatory response of immune cells. We studied the zymosan-binding potential of human dendritic cells (hDCs) by using specific carbohydrate inhibitors and blocking monoclonal antibodies. We show that DC-specific intercellular adhesion molecule-grabbing nonintegrin (DC-SIGN) is a major nonopsonic recognition receptor for zymosan on hDCs. Indeed, blocking of DC-SIGN inhibited the inflammatory response of DCs to zymosan. We compared the zymosan-binding capacity of hDC-SIGN to that of Dectin-1 and complement receptor 3 (CR3), which are receptors involved in the nonopsonic recognition of these yeast-derived particles. Dectin-1- and DC-SIGN-K562 cells bound to zymosan particles, whereas CR3-K562 cells did not. DC-SIGN and Dectin-1 were also expressed in COS cells to compare their ability to trigger particle internalization in a nonphagocytic cell line. DC-SIGN transfectants were unable to internalize bound particles, indicating that DC-SIGN is primarily involved in recognition but not in particle internalization. Zymosan induced a rapid DC aggregation that was accompanied by a dramatic change of DC-SIGN distribution in the plasma membrane. Under resting conditions, DC-SIGN was diffusely distributed through the cell surface, displaying clusters at the free leading edge. Upon zymosan treatment, DC-SIGN was markedly redistributed to cell-cell contacts, supporting an adhesion role in DC-DC interactions. The mechanism(s) supporting DC-SIGN-mediated intercellular adhesion were further investigated by using DC-SIGN-K562 aggregation. DC-SIGN was highly concentrated at points of cell-cell contact, suggesting a role for enhanced avidity during DC-SIGN-mediated intercellular adhesion.
Assuntos
Moléculas de Adesão Celular/imunologia , Comunicação Celular/imunologia , Células Dendríticas/imunologia , Lectinas Tipo C/imunologia , Fagocitose/imunologia , Receptores de Superfície Celular/imunologia , Zimosan/farmacologia , Animais , Células COS , Agregação Celular/imunologia , Membrana Celular/imunologia , Chlorocebus aethiops , Células Dendríticas/fisiologia , Humanos , Células K562 , Antígeno de Macrófago 1/imunologia , Proteínas de Membrana/imunologia , Monócitos/imunologia , Monócitos/fisiologia , Proteínas do Tecido Nervoso/imunologia , Leveduras/imunologia , Zimosan/imunologiaRESUMO
Dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN) is a type II C-type lectin that functions as an adhesion receptor and mediates binding and internalization of pathogens such as virus (human immunodeficiency virus, hepatitis C), bacteria (Mycobacterium), fungi, and parasites. DC-SIGN expression in vivo is primarily restricted to interstitial dendritic cells (DC) and certain tissue macrophages. We now report that leukemic THP-1 cells, widely used as a model for monocyte-macrophage differentiation, express very low basal levels of DC-SIGN and that DC-SIGN expression in THP-1 cells is regulated during differentiation. Differentiation-inducing agents (phorbol ester, bryostatin) conveyed THP-1 cells with the ability to up-regulate DC-SIGN mRNA levels and cell surface expression in response to interleukin-4 (IL-4) or IL-13. DC-SIGN up-regulation required a functional JAK-STAT signaling pathway, was inhibited in the presence of lipopolysaccharide (LPS) or tumor necrosis factor-alpha (TNF-alpha), and conferred THP-1 cells with increased pathogen recognition and T cell stimulatory capabilities. The up-regulation of DC-SIGN on THP-1 cells resembles its inducible expression on monocytes and macrophages, where DC-SIGN expression is also induced by IL-4/IL-13 and negatively regulated by TNF-alpha, LPS, and vitamin D(3). These results point to THP-1 cells as a useful cellular system to characterize the pathogen-binding capabilities of DC-SIGN and to dissect the molecular mechanisms that control its regulated and tissue-specific expression in myeloid dendritic cells, and the results suggest that DC-SIGN constitutes a marker for both DC and alternatively activated macrophages.
Assuntos
Moléculas de Adesão Celular/genética , Regulação da Expressão Gênica , Lectinas Tipo C/genética , Leucemia/metabolismo , Macrófagos/metabolismo , Monócitos/metabolismo , Receptores de Superfície Celular/genética , Linhagem Celular Tumoral , Humanos , Interleucina-4/farmacologia , Ativação de Macrófagos , Transdução de Sinais , Regulação para CimaRESUMO
Acquisition of CCR7 expression is an important phenotype change during dendritic cell (DC) maturation that endows these cells with the capability to migrate to lymph nodes. We have analyzed the possible role of CCR7 on the regulation of the survival of DCs. Stimulation with CCR7 ligands CCL19 and CCL21 inhibits apoptotic hallmarks of serum-deprived DCs, including membrane phosphatidylserine exposure, loss of mitochondria membrane potential, increased membrane blebs, and nuclear changes. Both chemokines induced a rapid activation of phosphatidylinositol 3'-kinase/Akt1 (PI3K/Akt1), with a prolonged and persistent activation of Akt1. Interference with PI3K, Gi, or G protein betagamma subunits abrogated the effects of the chemokines on Akt1 activation and on survival. In contrast, inhibition of extracellular signal-related kinase 1/2 (Erk1/2), p38, or c-Jun N-terminal kinase (JNK) was ineffective. Nuclear factor-kappaB (NFkappaB) was involved in the antiapoptotic effects of chemokines because inhibition of NFkappaB blunted the effects of CCL19 and CCL21 on survival. Furthermore, chemokines induced down-regulation of the NFkappaB inhibitor IkappaB, an increase of NFkappaB DNA-binding capability, and translocation of the NFkappaB subunit p65 to the nucleus. In summary, in addition to its well-established role in chemotaxis, we show that CCR7 also induces antiapoptotic signaling in mature DCs.
Assuntos
Apoptose/fisiologia , Células Dendríticas/citologia , Receptores de Quimiocinas/fisiologia , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/fisiologia , Células Dendríticas/ultraestrutura , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Microscopia Eletrônica de Varredura , NF-kappa B/fisiologia , Toxina Pertussis/farmacologia , Receptores CCR7 , Proteínas Recombinantes , Transdução de Sinais/fisiologia , TransfecçãoRESUMO
Tissue invasion by tumor cells involves their migration across basement membranes through activation of extracellular matrix degradation and cell motility mechanisms. Chemokines binding to their receptors provide chemotactic cues guiding cells to specific tissues and organs; they therefore could potentially participate in tumor cell dissemination. Melanoma cells express CXCR4, the receptor for the chemokine stromal cell-derived factor-1alpha (SDF-1alpha). Using Matrigel as a model, we show that SDF-1alpha promotes invasion of melanoma cells across basement membranes. Stimulation of membrane-type 1 matrix metalloproteinase (MT1-MMP) activity by SDF-1alpha was necessary for invasion, involving at least up-regulation in the expression of this metalloproteinase, as detected in the highly metastatic BLM melanoma cell line. Moreover, SDF-1alpha triggered the activation of the GTPases RhoA, Rac1, and Cdc42 on BLM cells, and expression of dominant-negative forms of RhoA and Rac1, but not Cdc42, substantially impaired the invasion of transfectants in response to SDF-1alpha, as well as the increase in MT1-MMP expression. Furthermore, CXCR4 expression on melanoma cells was notably augmented by transforming growth factor-beta1, a Matrigel component, whereas anti-transforming growth factor-beta antibodies inhibited increases in CXCR4 expression and melanoma cell invasion toward SDF-1alpha. The identification of SDF-1alpha as a potential stimulatory molecule for MT1-MMP as well as for RhoA and Rac1 activities during melanoma cell invasion, associated with an up-regulation in CXCR4 expression by interaction with basement membrane factors, could contribute to better knowledge of mechanisms stimulating melanoma cell dissemination.
Assuntos
Quimiocinas CXC/fisiologia , Melanoma/enzimologia , Melanoma/patologia , Metaloendopeptidases/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo , Membrana Basal/enzimologia , Linhagem Celular Tumoral , Quimiocina CXCL12 , Quimiocinas CXC/metabolismo , Quimiocinas CXC/farmacologia , Ativação Enzimática , Humanos , Metástase Linfática , Metaloproteinases da Matriz Associadas à Membrana , Melanoma/genética , Melanoma/metabolismo , Metaloendopeptidases/biossíntese , Metaloendopeptidases/genética , Invasividade Neoplásica , Receptores CXCR4/biossíntese , Receptores CXCR4/genética , Transfecção , Fator de Crescimento Transformador beta/farmacologia , Fator de Crescimento Transformador beta1 , Regulação para Cima/efeitos dos fármacos , Proteína cdc42 de Ligação ao GTP/genética , Proteína cdc42 de Ligação ao GTP/metabolismo , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteínas rho de Ligação ao GTP/biossíntese , Proteínas rho de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismoRESUMO
Kidins220, a protein predominantly expressed in neural tissues, is the first physiological substrate for protein kinase D (PKD). We show that Kidins220 is expressed in monocyte-derived and in peripheral blood immature dendritic cells (im DC). Immature DC (im DC) migrate onto extracellular matrices changing cyclically from a highly polarized morphology (monopolar (MP) stage) to a morphologically symmetrical shape (bipolar (BP) stage). Kidins220 was localized on membrane protrusions at the leading edge or on both poles in MP and BP cells, respectively. CD43, CD44, ICAM-3 and DC-SIGN, and signaling molecules PKD, Arp2/3 were found at the leading edge in MP or on both edges in BP cells, showing an intriguing parallelism between morphology and localization of molecular components on the poles of the motile DC. F-actin co-localized and it was necessary for Kidins220 localization on the membrane in MP and BP cells. Kidins220 was also found in a raft compartment. Disruption of rafts with methyl-beta-cyclodextrin induced rounding of the cells, inhibition of motility and lost of Kidins220 polarization. Our results describe for the first time the molecular components of the poles of motile im DC and indicate that a novel neuronal protein may be an important component among these molecules.
Assuntos
Diferenciação Celular/fisiologia , Células Dendríticas/metabolismo , Microdomínios da Membrana/metabolismo , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Fosfoproteínas/metabolismo , Actinas/metabolismo , HumanosRESUMO
The monocyte capacity to differentiate into dendritic cells (DCs) was originally demonstrated by human in vitro DC differentiation assays that have subsequently become the essential methodologic approach for the production of DCs to be used in DC-mediated cancer immunotherapy protocols. In addition, in vitro DC generation from monocytes is a powerful tool to study DC differentiation and maturation. However, whether DC differentiation from monocytes occurs in vivo remains controversial, and the physiologic counterparts of in vitro monocyte-derived DCs are unknown. In addition, information on murine monocytes and monocyte-derived DCs is scarce. Here we show that mouse bone marrow monocytes can be differentiated in vitro into DCs using similar conditions as those defined in humans, including in vitro cultures with granulocyte-macrophage colony-stimulating factor and interleukin 4 and reverse transendothelial migration assays. Importantly, we demonstrate that after in vivo transfer monocytes generate CD8- and CD8+ DCs in the spleen, but differentiate into macrophages on migration to the thoracic cavity. In conclusion, we support the hypothesis that monocytes generate DCs not only on entry into the lymph and migration to the lymph nodes as proposed, but also on extravasation from blood and homing to the spleen, suggesting that monocytes represent immediate precursors of lymphoid organ DCs.
Assuntos
Antígenos CD8/análise , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Células Dendríticas/imunologia , Monócitos/imunologia , Baço/imunologia , Animais , Células da Medula Óssea/imunologia , Linfócitos T CD8-Positivos/fisiologia , Movimento Celular , Células Cultivadas , Proteínas de Ligação a DNA/genética , Células Dendríticas/citologia , Células Dendríticas/fisiologia , Endotélio Vascular/fisiologia , Humanos , Imunofenotipagem , Teste de Cultura Mista de Linfócitos , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Monócitos/citologia , Monócitos/fisiologia , Receptores de Superfície Celular/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Receptor Toll-Like 9 , Receptores Toll-Like , Veias UmbilicaisRESUMO
Distinct subsets of dendritic cells (DCs) are present in blood, probably "en route" to different tissues. We have investigated the chemokines and adhesion molecules involved in the migration of myeloid (CD11c(+)) and plasmacytoid (CD123(+)) human peripheral blood DCs across vascular endothelium. Among blood DCs, the CD11c(+) subset vigorously migrated across endothelium in the absence of any chemotactic stimuli, whereas spontaneous migration of CD123(+) DCs was limited. In bare cell migration assays, myeloid DCs responded with great potency to several inflammatory and homeostatic chemokines, whereas plasmacytoid DCs responded poorly to all chemokines tested. In contrast, the presence of endothelium greatly favored transmigration of plasmacytoid DCs in response to CXCL12 (stromal cell-derived factor-1) and CCL5 (regulated on activation, normal T expressed and secreted). Myeloid DCs exhibited a very potent transendothelial migration in response to CXCL12, CCL5, and CCL2 (monocyte chemoattractant protein-1). Furthermore, we explored whether blood DCs acutely switch their pattern of migration to the lymph node-derived chemokine CCL21 (secondary lymphoid-tissue chemokine) in response to microbial stimuli [viral double-stranded (ds)RNA or bacterial CpG-DNA]. A synthetic dsRNA rapidly enhanced the response of CD11c(+) DCs to CCL21, whereas a longer stimulation with CpG-DNA was needed to trigger CD123(+) DCs responsive to CCL21. Use of blocking monoclonal antibodies to adhesion molecules revealed that both DC subsets used platelet endothelial cell adhesion molecule-1 to move across activated endothelium. CD123(+) DCs required beta(2) and beta(1) integrins to transmigrate, whereas CD11c(+) DCs may use integrin-independent mechanisms to migrate across activated endothelium.
Assuntos
Moléculas de Adesão Celular/farmacologia , Quimiocinas/farmacologia , Citocinas , Células Dendríticas/citologia , Peptídeos e Proteínas de Sinalização Intercelular , Anticorpos Monoclonais/farmacologia , Antígeno CD11c/análise , Antígenos CD18/imunologia , Antígenos CD18/fisiologia , Adesão Celular , Moléculas de Adesão Celular/antagonistas & inibidores , Moléculas de Adesão Celular/imunologia , Movimento Celular/efeitos dos fármacos , Quimiocina CCL11 , Quimiocina CCL19 , Quimiocina CCL2/farmacologia , Quimiocina CCL21 , Quimiocina CCL5/farmacologia , Quimiocina CCL7 , Quimiocina CXCL10 , Quimiocina CXCL11 , Quimiocina CXCL12 , Quimiocina CXCL9 , Quimiocinas/antagonistas & inibidores , Quimiocinas/imunologia , Quimiocinas CC/farmacologia , Quimiocinas CXC/farmacologia , Quimiotaxia/efeitos dos fármacos , Ilhas de CpG/imunologia , Células Dendríticas/classificação , Endotélio Vascular/citologia , Humanos , Integrina beta1/imunologia , Integrina beta1/fisiologia , Molécula 1 de Adesão Intercelular/fisiologia , Subunidade alfa de Receptor de Interleucina-3 , Proteínas Quimioatraentes de Monócitos/farmacologia , Células Mieloides/citologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/imunologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/fisiologia , RNA de Cadeia Dupla/síntese química , RNA de Cadeia Dupla/farmacologia , Receptores de Interleucina-3/análise , Proteínas Recombinantes/farmacologiaAssuntos
Interferon-alfa/efeitos adversos , Melanoma/tratamento farmacológico , Oligospermia/induzido quimicamente , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Relação Dose-Resposta a Droga , Esquema de Medicação , Seguimentos , Humanos , Interferon alfa-2 , Interferon-alfa/uso terapêutico , Masculino , Melanoma/patologia , Estadiamento de Neoplasias , Oligospermia/fisiopatologia , Proteínas Recombinantes , Medição de Risco , Neoplasias Cutâneas/patologia , Contagem de EspermatozoidesAssuntos
Movimento Celular/fisiologia , Células Dendríticas/fisiologia , Endotélio Vascular/fisiologia , Receptores de Fibronectina/metabolismo , Humanos , Integrina alfa4beta1 , Integrinas/metabolismo , Receptores de Retorno de Linfócitos/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
Dendritic cell-specific ICAM-3 grabbing nonintegrin (DC-SIGN) is a monocyte-derived dendritic cell (MDDC)-specific lectin which participates in dendritic cell (DC) migration and DC-T lymphocyte interactions at the initiation of immune responses and enhances trans-infection of T cells through its HIV gp120-binding ability. The generation of a DC-SIGN-specific mAb has allowed us to determine that the acquisition of DC-SIGN expression during the monocyte-DC differentiation pathway is primarily induced by IL-4, and that GM-CSF cooperates with IL-4 to generate a high level of DC-SIGN mRNA and cell surface expression on immature MDDC. IL-4 was capable of inducing DC-SIGN expression on monocytes without affecting the expression of other MDDC differentiation markers. By contrast, IFN-alpha, IFN-gamma, and TGF-beta were identified as negative regulators of DC-SIGN expression, as they prevented the IL-4-dependent induction of DC-SIGN mRNA on monocytes, and a similar inhibitory effect was exerted by dexamethasone, an inhibitor of the monocyte-MDDC differentiation pathway. The relevance of the inhibitory action of dexamethasone, IFN, and TGF-beta on DC-SIGN expression was emphasized by their ability to inhibit the DC-SIGN-dependent HIV-1 binding to differentiating MDDC. These results demonstrate that DC-SIGN, considered as a MDDC differentiation marker, is a molecule specifically expressed on IL-4-treated monocytes, and whose expression is subjected to a tight regulation by numerous cytokines and growth factors. This feature might help in the development of strategies to modulate the DC-SIGN-dependent cell surface attachment of HIV for therapeutic purposes.