Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

In this report, we present evidence that the CTL response directed against MHC Class I allo-determinants can be inhibited as a result of IL-10 expression in vivo. The presence of localized IL-10 secretion at the site of allogeneic tumor cell challenge resulted in marked inhibition of the CTL response and allowed growth of the tumor in the allogeneic host. Using purified CD4+ T cells from mice immunized in the presence or absence of IL-10, we have shown that the loss of alloreactivity as a consequence of IL-10 expression results from the inhibition of CD4+ T cell function. The expression of either IL-2 or IFN-gamma with IL-10 locally at the time of allogeneic cell challenge completely restored CTL alloreactivity, suggesting that the action of IL-10 could be bypassed by providing helper T lymphocyte-derived cytokines of the Th1 type at the site of immunization. Inhibition of alloreactivity by IL-10 was observed using either purified macrophages or dendritic cells as APC in an in vitro assay. Thus, the expression of IL-10 following antigenic challenge (such as that observed in Th2-like immune responses) may profoundly limit the ability for generating functional CTL in vivo.
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PMID:IL-10 inhibits alloreactive cytotoxic T lymphocyte generation in vivo. 799 51

IL-10 has previously been shown to inhibit cytokine production by Th1 cells by blocking macrophage accessory cell function. In this study we demonstrate that dendritic cell-induced Th1 proliferation was unaffected by IL-10, whereas macrophage-stimulated proliferation was inhibited in the same system. In contrast dendritic cell induced IFN-gamma production by the Th1 clones was down-regulated by IL-10. Inasmuch as dendritic cells have been shown to be potent APC for T cells in primary responses we determined the effect of IL-10 on dendritic cell-induced proliferation and IFN-gamma production by CD4+ and CD8+ T cells. Dendritic cells were effective at stimulating both proliferation and IFN-gamma secretion of CD4+ or CD8+ T cells in a primary allogeneic mixed leukocyte response. In contrast, IL-10 markedly inhibited dendritic cell driven IFN-gamma production by purified CD4+ and CD8+ T cells. Down-regulation of dendritic cell-induced IFN-gamma production suggests a role for IL-10 in inhibiting the initiation of cell-mediated immune responses.
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PMID:Differential effect of IL-10 on dendritic cell-induced T cell proliferation and IFN-gamma production. 809 24

IL-10 is a product of activated keratinocytes and is released during the induction phase of contact sensitivity. As IL-10 effects have been described as being mediated by APC, we investigated effects of IL-10 on epidermal Langerhans cells (LC), the resident APC in the epidermis. Initial studies failed to demonstrate effects of IL-10 on MHC class II Ag expression by LC or anti-CD3 mAb- or alloantigen-induced LC-dependent T cell proliferation. However, production of IFN-gamma and IL-2, (but not IL-6) was markedly reduced in these assays. When the soluble-protein Ag specific T cell clones AE7 (Th1) and D10.G4 (Th2) were substituted for unprimed T cells, differential effects of IL-10 on T-cell proliferation were observed. Whereas IL-10-pretreated and untreated LC supported Th2 cell proliferation equally well, IL-10-pretreated LC were essentially unable to induce Th1 cell proliferation in response to native protein or peptide Ag. The inhibitory influence of IL-10 on Th1 cells was observed when fresh or 1 day cultured LC were used; 2- or 3-day cultured LC were affected to a much lesser extent by IL-10 pretreatment. Further, coculture experiments using IL-10-pretreated or untreated LC of a different haplotype suggest that IL-10 negatively regulates a costimulatory signal required for induction of Th1 cell proliferation. To assess whether T cells incubated with Ag and IL-10-pretreated LC were responsive to further stimulation, T cells were rescued after 1 day of coculture with IL-10-pretreated LC and restimulated, either immediately or after 1 to 5 days of rest, with untreated LC in the presence of Ag. T cells incubated with IL-10-pretreated LC were found to be anergic, whereas T cells incubated with untreated LC proliferated normally after further stimulation. However, anergic T cells responded vigorously to IL-2. These data indicate that although IL-10-pretreated LC are effective APC for Th2 cells, they fail to induce Th1 cell proliferation and rather induce clonal anergy in these cells.
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PMID:Inhibition of Langerhans cell antigen-presenting function by IL-10. A role for IL-10 in induction of tolerance. 810 65

In hypovitaminosis A, Ab-mediated immunity is severely impaired. We reported that Trichinella spiralis infection stimulates a strong Th2 cell response in control mice but in vitamin A-deficient mice it stimulates a strong Th1 cell response. Here we investigated the immunobiologic mechanisms underlying this shift from a Th2- to a Th1-dominated response. A kinetic analysis showed that the Th1 cells developed first and IFN-gamma secretion predominated in deficient mice, whereas the Th2 cells developed later and IL-5 and IL-10 secretion predominated in control mice. The IFN-gamma-secreting cell frequencies were the same but cells from deficient mice secreted IFN-gamma sixfold faster than cells from control mice, and retinoic acid addition in vitro decreased that rate 50%. In contrast, the IL-5-secretion rates were the same but the IL-5-secreting cell frequency was lower in deficient mice than in controls, and retinoic acid addition in vitro doubled this frequency independently of its inhibitory effect on IFN-gamma. The APC from deficient mice stimulated greater IFN-gamma release than control APC and retinoic acid addition in vitro decreased this activity 50%. Together these results identify at least three vitamin A activities that balance Th1 and Th2 functions, down-regulating Th1 cell IFN-gamma secretion directly, decreasing activated APC function, and promoting Th2 cell growth and/or differentiation. In this system and perhaps others, the imbalance between regulatory Th1 and Th2 cells is one mechanism underlying poor Ab-mediated immunity in hypovitaminosis A.
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PMID:In vitamin A deficiency multiple mechanisms establish a regulatory T helper cell imbalance with excess Th1 and insufficient Th2 function. 812 Mar 66

We previously have proposed that accessory cells from individuals infected with schistosomiasis induce unresponsiveness in specific Th-1 lymphocytes resulting in the immunologic down-regulation of egg-induced granulomatous inflammation characteristically seen in this disease. We now show that macrophages isolated from schistosomal egg granulomas (GM) fail to serve as stimulatory APC for cloned, murine schistosomal egg Ag (SEA)-specific, CD4+, Th-1-type lymphocytes, while being able to stimulate Th-2-type responses. Instead, GM render Th-1 cells unresponsive to restimulation. Based on these findings, we tested two approaches to down-regulate the granulomatous inflammation associated with a schistosomal challenge infection. First, active ectopic granuloma induction in response to Schistosoma mansoni eggs, but not to Ascaris lumbricoides eggs, resulted in a significant reduction of granulomatous disease in vivo, as well as in the inhibition of specific proliferation of mesenteric lymph node cells in vitro. Second, passive administration of purified GM, but not of normal peritoneal cells (PC), resulted, similarly, in significant reduction of granuloma size in vivo and specific lympho-proliferation in vitro. Moreover, cytokine analysis of supernatants from stimulated lymph node cells disclosed that the Th-1-derived cytokine IL-2 decreased to undetectable levels, at the same time as the Th-2-derived cytokines IL-4 and IL-10 increased, in animals receiving GM, in contrast to those receiving PC or no cells. These findings are consistent with the interpretation that accessory cells such as GM induce unresponsiveness in specific Th-1 cells that, in turn, results in the down-regulation of granulomatous schistosomal disease and its in vitro correlates.
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PMID:Macrophages from schistosomal egg granulomas induce unresponsiveness in specific cloned Th-1 lymphocytes in vitro and down-regulate schistosomal granulomatous disease in vivo. 812 Mar 94

Cells of the macrophage lineage are required to cope with bacterial infection and to serve as APC for T lymphocytes. Among the regulatory factors limiting the macrophage response to infection and the expansion of Ag-specific T cells, IL-10 has received recent attention. On monocytes/macrophages, IL-10 has been shown to inhibit the intracellular killing of bacteria, the secretion of cytokines, and the expression of MHC molecules. In the present study we have examined the effect of IL-10 on different APC obtained from the central nervous system. Both, astrocytes and microglial cells are in a resting state and require activation signals to express MHC class II and cytokine genes. Whereas IL-10 profoundly inhibits the IFN-gamma-induced expression of MHC class II Ag on microglial cells, it had no such effects on astrocytes. Nevertheless, IL-10 suppressed the MHC class II- and Ag-dependent proliferative response of T cells in the presence of both types of APC. As shown by the use of anti-IL-10 Abs, endogenously produced IL-10 influenced the function of microglia but not of astrocytes to serve as APC. IL-10 significantly inhibited the LPS-induced production of granulocyte-macrophage-CSF, macrophage-CSF, and IL-6 by both astrocytes and microglial cells. In contrast, the secretion of these cytokines by the two glial cell population was not altered by IL-10 when IL-1 beta, TNF-alpha, or viruses were used as stimuli.
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PMID:Antigen presentation in the central nervous system. The inhibitory effect of IL-10 on MHC class II expression and production of cytokines depends on the inducing signals and the type of cell analyzed. 814 79

Exposure to UV radiation suppresses tumor rejection and delayed-in-time hypersensitivity reactions and depresses splenic APC function. Because almost all of the UV radiation is absorbed in the upper layers of the skin, it appears unlikely the direct irradiation of APC can account for the impaired ability of splenic adherent cells to present Ag after total-body UV exposure. Because UV-irradiated keratinocytes release IL-10, and in light of the well-documented effects of IL-10 on Ag presentation, we tested the hypothesis that keratinocyte-derived IL-10 is responsible for the systemic impairment of APC function following UV exposure. Injecting supernatants from UV-irradiated keratinocytes suppressed the ability of splenic adherent cells to present Ag. Treating the supernatants with anti-IL-10 mAb neutralized the suppressive effect. Similarly, when splenic adherent cells were isolated from mice exposed to UV radiation, APC function was suppressed. Injecting the UV-irradiated animals with anti-IL-10 restored APC function. In addition, spleen cells from UV-irradiated mice did not efficiently present Ag to Th1 clones, and injecting anti-IL-10 after UV exposure restored APC function. The reverse was observed when spleen cells from UV-irradiated mice were used to present Ag to Th2 clones; in which case, UV exposure enhances APC function, and anti-IL-10 reverses this effect. These findings suggest that UV-induced, keratinocyte-derived IL-10 can modulate splenic APC function.
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PMID:Mechanism involved in the systemic suppression of antigen-presenting cell function by UV irradiation. Keratinocyte-derived IL-10 modulates antigen-presenting cell function of splenic adherent cells. 814 24

Egg Ag-stimulated lymphoid cell culture supernatants from schistosome-infected mice significantly inhibited Ag-specific, MHC-restricted proliferative responses of cloned schistosomal egg Ag-specific CD4+, Th-1-type lymphocytes. The inhibitory molecule in the supernatants was found to be the cytokine IL-10. Maximal IL-10 was produced by cells from mice carrying 8-wk schistosome infections, and none by cells from normal mice. IL-10 exerted its biologic activity on APC, and not directly on the cloned lymphocytes, resulting in the inhibition of Th-1 lymphocyte proliferation, whereas Th-2 responses were not affected. Most significantly, IL-10 also affected Th-1 clone activity in vivo, as measured by the inhibition of schistosomal egg Ag-specific local delayed-type hypersensitivity reactions. IL-10 produced in schistosome-infected individuals may play a role in the generation of APC, such as macrophages in schistosomal egg granulomas, unable to efficiently stimulate, but capable of inducing a state of anergy/unresponsiveness in Th-1 lymphocytes. We believe that this state of Th-1 cell anergy translates into the down-regulation of granulomatous hypersensitivity (immunomodulation) characteristically observed in the evolving schistosomal disease.
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PMID:Role of IL-10 on antigen-presenting cell function for schistosomal egg-specific monoclonal T helper cell responses in vitro and in vivo. 837 75

IL-10 gene transcription and IL-10 protein production was assessed in both type 1 (Th1) and type 2 (Th2) CD4+ human T cell clones by polymerase chain reaction and ELISA, respectively. Although Th2 clones apparently showed higher IL-10 mRNA levels, IL-10 mRNA expression was consistently found in Th1 clones, as well. Likewise, measurable IL-10 levels were found in the supernatants of both Th1 and Th2 clones. The effect of human IL-10 (h-IL-10) and viral IL-10 (v-IL-10) on the proliferative response and cytokine production by Th1 and Th2 human clones was also investigated. Addition in culture of h-IL-10 and v-IL-10 significantly reduced the proliferation of both Th1 and Th2 clones in response to the specific Ag and to PHA, but it had no inhibitory effect on the proliferative response of Th1 and Th2 clones to IL-2. h-IL-10 and v-IL-10 also inhibited the Ag-induced production of gamma-interferon (IFN-gamma) by Th1 clones and the production of IL-4 and IL-5 by Th2 clones, whereas they had no effect on the cytokine synthesis by the same clones stimulated with PMA plus anti-CD3 antibody. Preincubation of APC, but not of clonal T blasts, with h-IL-10 resulted in the inhibition of Ag-induced proliferation of both Th1 and Th2 clones, supporting the view that h-IL-10 primarily affects APC. These data demonstrate that, unlike the murine system where IL-10 is a product of Th2 (but not Th1) cells and seems to mainly down-regulate the Th1 response, in the human system, IL-10 is produced by, and down-regulates the function of, both Th1 and Th2 cells.
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PMID:Human IL-10 is produced by both type 1 helper (Th1) and type 2 helper (Th2) T cell clones and inhibits their antigen-specific proliferation and cytokine production. 841 68


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