Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06126 (CD1a)
 2,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To date no hematopoietic progenitors of dendritic Langerhans' cells (DLC), which represent an highly efficient class of antigen presenting cells, have been identified or the cytokines they elaborate have been defined. Here we describe an acute leukemia patient whose blasts (90-96% in peripheral blood and bone marrow) had a phenotype consistent with putative progenitors of DLC. The patient was treated with ara-C and VP-16 but did not achieve remission. The blasts had lobulated nuclei, no cytoplasmic vacuolation or Auer rods and were weakly positive for acid phosphatase and non-specific esterase and negative for PAS, granzyme A, dipeptidyl aminopeptidase IV, ATPase/ADPase and lysozyme production. The blasts were positive for CD1a, CD4, CD16, CD35, HLADR, HLADQ, CD11b, CD11c, CD14, CD33, CD34, CD11a, CD71, CD19, CD25, IL-2R beta and negative for CD2, CD7, CD8, CD10, CD22, CD56, CD57, surface or cytoplasmic CD3, TCR delta and TCR beta, HTLV-1p19 and P-glycoprotein. On liquid culture with or without 5 x 10(-9) M 12-O-tetradecanoylphorbol-13-acetate (TPA) for 3 days, the blasts formed aggregates of proliferating and elongating cells on the wall of the flasks with a decline in CD34, numerous dendritic processes appeared on the cells and there was strong positivity for ATPase/ADPase, but no other changes in phenotype. No macrophages were observed, indicating derivation from separate DLCs. Cytogenetic analysis showed chromosomal abnormalities and electron microscopy showed Birbeck granules. Southern blotting of DNA showed rearrangement of one allele for both JH and TCR beta but no HTLV-1 related sequences. Culture supernatants from blasts cultured with or without TPA showed the production of large amounts of IL-8, IL-6, TNF-alpha, MIP-1 alpha, IL-10 and interferon gamma and modest amounts of IL-1 alpha, GM-CSF and stem cell factor. The presence not only of CD1a, HLADR, HLADQ and many other characteristics including Birbeck granules, but also differentiation along the lines of DLC with appearance of dendritic processes on the cells and expression of ATPase/ADPase activity, indicate that the leukemic blasts in our patient represented a leukemic counterpart of normal progenitors of DLC and the leukemia a new entity which could possibly be classified as AML-M8. Lastly, many pro-inflammatory cytokines produced by DLC could contribute to inflammation and IL-10 to immunosuppression.
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PMID:Phenotype, genotype and cytokine production in acute leukemia involving progenitors of dendritic Langerhans' cells. 791 55

Because activated human macrophages can be potent sources of IL-10, and because immunosuppressive tolerance-inducing macrophages populate the skin after UV exposure, we determined whether IL-10 is induced after UV exposure of human skin and whether it is related to the immigrating macrophages. Keratomes were obtained from control skin or from skin obtained 72 h after a single exposure to four minimal erythemal doses of UVB. Quantitative reverse-transcriptase PCR on total RNA extracted immediately from skin keratomes showed that IL-10 mRNA was elevated in UV-exposed skin. Epidermal cell suspensions from non-UV-exposed keratomes (C-EC) and UV-exposed keratomes (UV-EC) were fractionated by sequential immunobead selection. IL-10 mRNA was reproducibly 200- to 400-fold higher in CD11b+ UV-EC (macrophages) relative to CD11b- UV-EC (keratinocytes). IL-10 mRNA was not detected in C-EC that contained the CD1a+ population (Langerhans cells) nor in CD1a- C-EC keratinocytes from normal skin. As determined by ELISA, CD11b+ UV-EC IL-10 cell-associated protein was fivefold higher than that of CD11b- UV-EC; this was confirmed by flow cytometric visualization of IL-10 protein in permeabilized cells. CD11b+ UV-EC macrophages secreted IL-10 protein into the supernatant at a level of 333 +/- 51 pg/10(6) cells, whereas UV-EC keratinocytes did not secrete detectable levels of IL-10 (n = 3), although UV did induce low levels of IL-10 mRNA and cell-associated protein in keratinocytes. Therefore, although human keratinocytes accumulate intracellular IL-10 after in vivo UV exposure, the most potent production and secretion of IL-10 in the epidermis seems to be that of UV-induced macrophages. Skin-infiltrating macrophage secretion of such a potent immunoregulatory cytokine may account for the delayed immunosuppressive environment of sunburned skin and the altered APC activity of the infiltrating macrophages.
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PMID:CD11b+ macrophages that infiltrate human epidermis after in vivo ultraviolet exposure potently produce IL-10 and represent the major secretory source of epidermal IL-10 protein. 796 79

Dendritic cells are potent stimulators of Ag-specific T cell responses and have been implicated in the pathogenesis of HIV-1 and other viral infections. Although cytokines may be involved in both of these processes, there is little information on the expression of cytokines by human blood dendritic cells. We characterized cytokine gene and protein expression in dendritic cells that were purified from normal human PBMC by flow cytometry and stimulated in vitro for up to 24 h with HIV-1 or herpes simplex virus (HSV). The unstimulated, uncultured dendritic cells were defined by their phenotype (HLA DR+ CD3- CD19- CD16- CD56- CD14-) and distinct morphology, lack of mRNA expression for CD3, CD14 and CD19, and presence of mRNA for CD4 and CD83. The purified dendritic cells also expressed CD4 (70-90%), CD33 (36-48%), and CD11c (44-54%); lacked CD1a expression (<1%); and were potent stimulators of an allogeneic MLR. The stimulated dendritic cells expressed mRNA for IFN-alpha, IL-1alpha, IL-1beta, IL-6, IL-10, IL-12, GM-CSF, and TNF-alpha within 4 to 12 h as determined by reverse transcription-PCR, with higher levels induced by HSV compared with HIV-1 strains IIIb or BaL. In contrast, the dendritic cells produced detectable protein only for IFN-alpha and IL-6 in response to HIV-1 or HSV, and IL-1beta in response to HSV within 24 h. There were no differences in expression of CD80 and CD86 surface molecules by dendritic cells that were either mock stimulated or stimulated with HIV-1 or HSV for 24 h. Production of IFN-alpha, IL-1beta, and IL-6 by dendritic cells may be important to the immunologic function of these cells and their role in the pathogenesis of HIV-1 and HSV infections.
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PMID:Cytokine expression by human peripheral blood dendritic cells stimulated in vitro with HIV-1 and herpes simplex virus. 889 36

We evaluated the effects of interleukin (IL)-10 on the differentiation of dendritic cells (DC) obtained by culturing plastic-adherent peripheral blood mononuclear cells for 7 days in presence of granulocyte/macrophage-colony-stimulating factor (GM-CSF) + IL-4. The addition of IL-10 at the initiation of culture resulted in the generation of macrophage-like cells with expressing high levels of CD14 and decreased levels of CD1a and CD1c. Furthermore, cells generated in presence of IL-10 secreted lower levels of IL-12, but higher levels of IL-8 compared with DC generated in absence of IL-10, both spontaneously and after CD40 engagement. Finally, cells generated in presence of IL-10 were less efficient than DC in stimulating the production of IL-2, interferon-gamma, and IL-4 by allogeneic T cells. We conclude that IL-10 prevents the generation of DC induced by GM-CSF + IL-4 and favors the development of macrophages with a lower T cell stimulatory potential, but secreting higher levels of IL-8 than DC.
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PMID:Interleukin-10 prevents the generation of dendritic cells from human peripheral blood mononuclear cells cultured with interleukin-4 and granulocyte/macrophage-colony-stimulating factor. 907 19

We compared dendritic cells (DC) derived from CD34+ hematopoietic progenitor cells with tumor necrosis factor alpha and granulocyte-macrophage colony-stimulating factor (GM-CSF) to DC derived from monocytes/macrophages with interleukin-4 (IL-4) and GM-CSF. Monocyte/macrophage-derived DC demonstrated higher levels of CD1a, lower levels of CD14, greater stimulatory activity in mixed lymphocyte reactions, and greater capacity to present soluble protein antigen than CD34+ cell-derived DC. Lymphocytes stimulated with antigen-pulsed, monocyte/macrophage-derived DC produced more IL-10 than those stimulated with antigen-pulsed, CD34+-derived DC. Whereas CD1a+ DC could be derived from CD34+ cells in serum-free- and human-sera-containing cultures, the derivation of CD1a+ DC from monocytes/macrophages required the presence of fetal calf serum. The spectrum of cytokine mRNA expression, the presentation of peptide antigen, and the sensitivity to human immunodeficiency virus-1 infection of CD34(+)- and monocyte/macrophage-derived DC were comparable. Although cells derived by both methods are potent antigen-presenting cells, there are differences between DC derived in vitro from hematopoietic progenitors and from monocytes/macrophages that may influence their in vivo activity.
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PMID:Phenotypic and functional differences between human dendritic cells derived in vitro from hematopoietic progenitors and from monocytes/macrophages. 912 9

We studied to what extent the presence of an inflammatory mediator PGE2, during the development of dendritic cells (DC) affects their subsequent ability to induce Th1- and Th2-type cytokines in maturing naive Th cells. PGE2 (10(-9)-10(-6) M) did not alter the morphology or the expression of class II MHC and costimulatory molecules on DC obtained from monocytes in the presence of granulocyte-macrophage CSF and IL-4, although at concentrations above 10(-8) M, PGE2 prevented the acquisition of CD1a marker. Both control DC and DC maturing in the presence of PGE2 (PGE2-DC) were potent stimulators of naive Th cells. In contrast to control DC, which produced high amounts of IL-12 and trace amounts of IL-10, PGE2-DC produced no IL-12 and high amounts of IL-10 when stimulated in the absence of PGE2. This distinct cytokine profile of PGE2-DC was stable for at least 48 h of additional culture in the absence of PGE2. Control DC induced the development of Th0-like cells from superantigen-activated naive Th cells, whereas PGE2-DC promoted the development of Th cells that produced high amounts of IL-4 and IL-5. Experiments using IL-12-neutralizing Abs or rIL-12 indicated a crucial role of IL-12 deficiency in the induction of type 2 cytokine profiles. These findings suggest that elevated levels of PGE2 promote type 2 Th responses by stably impairing the ability of maturing DC to produce IL-12. Since type 2 Th responses are protective in several Th1-related autoimmune disorders, PGE2-DC may be considered for use in immunotherapy.
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PMID:IL-12-deficient dendritic cells, generated in the presence of prostaglandin E2, promote type 2 cytokine production in maturing human naive T helper cells. 920 Apr 35

In order to investigate the impact of an inflammatory mediator PGE2 on the functions of maturing DC we used an in vitro model of DC generation from peripheral blood monocytes. Addition of PGE2 (10(-9) M-10(-6) M) to the cultures performed in the presence of GM-CSF and IL-4 did not alter the morphology nor high levels of expression of class II MHC and co-stimulatory molecules on arising DC, although at concentrations above 10(-8) M, the acquisition of CD1a was selectively prevented. Control DC and the DC maturing in the presence of PGE2 (PGE2-DC) induced a similar proliferation of naive Th cells. Control DC produced high amounts of IL-12, and only trace amounts of IL-10, whereas PGE2-DC produced no IL-12 and high levels of IL-10, when stimulated after the removal of PGE2. The deficient IL-12 production by PGE2-DC was observed after stimulation both in the absence and in the presence of IFN gamma, and was not compensated during further 48 h culture in the absence of PGE2. Compared to control DC, PGE2-DC induced development of Th cells secreting elevated amounts of IL-4 and IL-5, from naive precursors. These data indicate that elevated tissue levels of PGE2 may promote type 2 Th responses by impairing the ability of locally maturing DC to produce IL-12. Since Th2 responses mediate protection in Th1-related autoimmune disorders, the use of PGE2-DC in immunotherapy of such disorders may be considered.
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PMID:Dendritic cells, obtained from peripheral blood precursors in the presence of PGE2, promote Th2 responses. 928 87

Human monocytes cultured with granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-13 for 7 days differentiate into cells with the morphology and function of dendritic cells (DC). We have investigated the effect of IL-10 on this differentiation pathway. In the presence of IL-10 cells did not develop DC morphology, did not express CD1a and had lower levels of MHC class II. IL-10 promoted the differentiation of large cells with the morphology, cytochemistry and membrane phenotype of macrophages, including staining for nonspecific esterase and high levels of CD14, CD16 and CD68. The effect of IL-10 was dose dependent and was best appreciated when the cytokine was added at the initiation of the culture, as addition on day 3 was less inhibitory. When added to already differentiated DC on day 6, IL-10 caused only a modest reduction of MHC class II and CD1a expression, and no acquisition of the macrophage markers CD14, CD16 and CD68. Prolonged incubation up to 5 days with IL-10 did not induce a shift of differentiated DC to macrophages. On the other hand, the macrophages obtained by culturing for 7 days with GM-CSF+IL-13+IL-10 did not shift to DC upon removal of IL-10 for up to 3 days. Thus, the effect of IL-10 on monocyte differentiation, occurs only at the precursor level and confers an irreversible phenotype. From a functional point of view, cells cultured in the presence of IL-10 were poor stimulators of allogeneic cord blood T cells in mixed lymphocyte reaction (MLR) and presented tetanus toxin (TT) to specific T cell lines with much less efficiency than control DC. In contrast, IL-10-cultured DC showed 7 times greater endocytosis of FITC-dextran. This increased endocytosis was mostly mediated via the mannose receptor, as demonstrated by blocking with unlabeled mannose. In conclusion, IL-10 inhibits DC differentiation from monocytes and, in a substantial proportion of the cells, promotes the differentiation to mature macrophages. Intriguingly, IL-10 inhibits antigen presentation while it stimulates endocytic activity.
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PMID:IL-10 prevents the differentiation of monocytes to dendritic cells but promotes their maturation to macrophages. 948 15

Dermatofibroma is composed largely of interlacing fascicles of slender spindle cells set within a loose collagenous stroma and of scattered foamy histiocytes and multinucleated giant cells. There is clear evidence indicating that factor XIIIa+ dermal dendritic cells (DDCs) are the cells constituting dermatofibromas. However, it is still unknown what stimulation is responsible for transforming DDCs into different cell types, producing different subtypes of dermatofibromas. Recently, it has become possible to obtain dendritic cells (DCs), that are identical with DDCs in their phenotypic and functional characteristics, from the culture of CD14+ peripheral blood monocytes to which IL-4 and GM-CSF were added. Using these monocyte-derived DCs, we examined the ability of various cytokines, such as IL-1beta , IL-3, IL-5, IL-6, IL-7, IL-8, IL-10, TNFalpha, TGFbeta, M-CSF, IFNalpha, and IFNgamma, and phorbol 12-myristate 13-acetate (PMA), to induce different cell types observed in DFs. Among them, only PMA could induce a variety of cell types such as histiocytic cells, fibroblastic spindle-shaped cells, and even multinucleated giant cells of Touton or foreign body type. Phenotypically, all the induced cell types expressed CD1a, CD80, CD86, HLA-DR, and CD68 in a magnitude similar to that of non-treated monocyte-derived DCs. The expression of factor XIIIa was strongest in histiocytic cells, moderate in fibroblastic cells, and weakest or negative in giant cells. These data suggest that dermatofibromas are a kind of neoplastic disease which is induced only by the effect of some tumor promoter on DDCs.
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PMID:Phorbol 12-myristate 13-acetate can transform monocyte-derived dendritic cells to different cell types similar to those found in dermatofibroma. A possible in vitro model of the histogenesis of dermatofibroma. 952 94

Calcipotriene is a synthetic analogue of 1,25-dihydroxyvitamin D3 established to be effective topically in the treatment of psoriasis. We investigated the early cellular and immunological events induced by calcipotriene in psoriasis. Thirty patients with moderate plaque-type psoriasis were randomly assigned to receive twice daily applications of either calcipotriene ointment 0.005% or matching vehicle for 6 weeks. Skin biopsies (6 mm) were performed from designated plaques at baseline and days 3 and 7. On these days and at weeks 2, 4 and 6, complete clinical evaluations were made in a double-blind fashion. Consistent with previous studies, significant clinical improvement (P < 0.05) in psoriasis was observed in patients receiving calcipotriene vs. those receiving vehicle by day 7 for scale and erythema, and by day 14 for thickness. No significant improvement, however, was seen on day 3. None of the immunohistological markers (CD1a, CD4, CD8, ICAM-1, VCAM-1, E-selectin, HLA-DR) semiquantitatively assessed in psoriatic plaques was significantly changed by calcipotriene treatment for 7 days. In the calcipotriene-treated group, interleukin (IL)-10 levels (pg/microgram of protein) increased by 57% from baseline (0.030 +/- 0.006; mean +/- SEM) to day 3 (0.047 +/- 0.011) (P = 0.05 vs. baseline; n = 10) and remained elevated at day 7 (0.046 +/- 0.012). IL-8 levels (pg/microgram of protein), however, declined by 70% from baseline (0.13 +/- 0.06) to day 3 (0.04 +/- 0.01), and remained low at day 7 (0.03 +/- 0.02) (P < 0.05 vs. baseline; n = 10). Both IL-8 and IL-10 were unaffected by vehicle treatment. Calcipotriene-induced clinical improvement of psoriasis is preceded by an increase in IL-10 and a concomitant decrease in IL-8 levels. The changes in the level of these two cytokines provide further evidence for immunological changes as a significant part of the mechanism of action of calcipotriene in psoriasis.
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PMID:Calcipotriene-induced improvement in psoriasis is associated with reduced interleukin-8 and increased interleukin-10 levels within lesions. 953 26


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