Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IL-12 is a 70-kDa heterodimeric cytokine composed of a p35 chain and p40 chain. This cytokine exerts a powerful positive regulatory influence on the development of Th1 helper T-cell immune responses and is a potent inducer of IFN-gamma production and cytotoxic T cell differentiation and function. Because epidermal Langerhans cells (LC) are important members of the dendritic APC lineage family critical for initiating cell mediated immune responses, we examined LC for their ability to produce IL-12. Epidermal cell (EC) suspensions obtained from volunteers were enriched for, or depleted of, Langerhans cells (CD1a+ EC). Enriched populations contained > 90% CD1a+ cells, whereas depleted populations contained < 1% CD1a+ cells. As assessed by reverse transcription-PCR amplification, IL-12 p40 mRNA was constitutively expressed in LC RNA extracted immediately following keratome harvest, and increased spontaneously after overnight incubation. Radioimmunoassay (RIA) of IL-12 p40 protein on supernatants revealed IL-12 release by CD1a-enriched fractions of epidermal cells. Ab specific for p40 clearly demonstrated IL-12 in epidermal LC by flow cytometry. A bioassay for the functional IL-12 heterodimer (p70) indicated that LC could produce IL-12 biologic activity, which was neutralized by anti-IL-12 Ab. These results indicate that epidermal LC, in particular cultured LC maturing into dendritic cells, express IL-12 p40 mRNA, as well as p40 and functional p70 protein, and suggest that this is one mechanism behind the high potency of dendritic APCs, such as LC, to initiate Th1 type immune responses under appropriate conditions.
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PMID:IL-12 synthesis by human Langerhans cells. 856 40

The capacity of APC to stimulate the proliferation of human peripheral blood T cells decreases upon ultraviolet-B (UVB) irradiation. The aim of this study was to investigate whether all T cell subsets are equally sensitive to this reduced APC function. Established human Th1, Th2, and Th0 clones were stimulated with monocytes in a soluble CD3 mAb-mediated assay that is dependent on the presence of APC. Monocytes were exposed to low nonlethal doses of UVB radiation before coculture with T cells. UVB irradiation inhibited the capacity of monocytes to stimulate the proliferation and IFN-gamma production of Th1 cells in a dose-related fashion. In contrast, UVB-treated monocytes induced normal proliferation and IL-4 production in Th2 cells. Stimulation of Th0 cell proliferation by UVB-irradiated monocytes was normal, but a preferential suppression of IFN-gamma production was observed, thus leading to a more Th2-like cytokine response. The loss of Th1 proliferation upon stimulation with UVB-irradiated monocytes could be overcome by rIL-2; however, IFN-gamma production remained suppressed. IFN-gamma production could be completely restored by rIL-12, whereas the addition of IL-1 beta, TNF-alpha, or indomethacin had no such effect, nor did the addition of mAb to CD28, added to compensate for the reduced B7 expression of UVB-irradiated monocytes. Monocytes exposed to UVB radiation exhibited reduced expression of mRNA for the IL-1 2 subunits p35 and p40 and suppressed production of the IL-12 p70 protein. Our results thus indicate that UVB irradiation of APC selectively impairs Th1-like responses, a phenomenon caused by the UVB-induced suppression of monocyte IL-12 production.
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PMID:Reduced IL-12 production by monocytes upon ultraviolet-B irradiation selectively limits activation of T helper-1 cells. 875 9

Dendritic cells (DC) are important initiators of specific primary immune responses because they are the only APC that can efficiently activate naive Th cells. DC have the capacity to produce interleukin-12 (IL-12), a cytokine that plays a pivotal role in the development of Th1-mediated cellular immune responses. The present study focuses on the conditions under which human DC produce bioactive IL-12 p70 and, consequently, direct the development of naive T helper (Th) cells toward the Th1 phenotype. Bacteria or bacterial compounds such as Staphylococcus aureus Cowan strain I (SAC) or lipopolysaccharide (LPS) induced substantial IL-12 levels in DC, which could be further upregulated by interferon-gamma (IFN-gamma), whereas induction of IL-12 production via CD40 ligation required IFN-gamma as an obligatory, complementary signal. Also, activated naive Th cells were poor inducers of IL-12 production, unless exogenous IFN-gamma was present, whereas activated memory Th cells were effective inducers of IL-12 production and did not require exogenous IFN-gamma. Next, the cytokine profiles of matured Th cells that were primed by DC under different conditions were examined. DC promoted the development of naive Th cells into memory Th0 cells that produced both the type 1 cytokine IFN-gamma and the type 2 cytokine IL-4. In contrast, after activation with SAC, DC efficiently directed the development of Th1 cells through the release of IL-12. An APC-independent Th cell maturation model, using either recombinant IL-12 or supernatants of SAC-activated DC and neutralizing anti-IL-12 antibodies, confirmed that DC-derived IL-12 was the major Th1 skewing factor. Together, these data indicate that the contact between DC and naive Th cells during the initiation of specific immune responses does not result in the efficient induction of IL-12 production and that, consequently, exogenous IL-12-inducing factors are required to promote primary Th1-mediated cellular immune responses.
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PMID:Human dendritic cells require exogenous interleukin-12-inducing factors to direct the development of naive T-helper cells toward the Th1 phenotype. 929 25

Th1-polarized CD4+ T cells are considered central to the development of a number of target-directed autoimmune disorders including multiple sclerosis. The APC-derived cytokine IL-12 is a potent inducer of Th1 polarization in T cells. Inhibition of IL-12 in vivo blocks the development of experimental allergic encephalomyelitis, the animal model for multiple sclerosis. Based on previous work that suggests that the production of IL-12 by activated human central nervous system-derived microglia is regulated by autocrine TNF-alpha, we wanted to determine whether inhibition of TNF could induce a reduction of Th1 responses by its impact on systemic APCs. We found that soluble TNFR p75-IgG fusion protein (TNFR:Fc) inhibited production of IFN-gamma by allo-Ag-activated blood-derived human CD4 T cells. We documented reduced IL-12 p70 production by APCs in the MLR. By adding back recombinant IL-12, we could rescue IFN-gamma production, indicating that TNFR:Fc acts on APC-derived IL-12. Consistent with an inhibition of the Th1 polarization, we found a decreased expression of IL-12R-beta2 subunit on the T cells. Furthermore, the capacity of T cells to secrete IFN-gamma upon restimulation when previously treated with TNFR:Fc is impaired, whereas IL-2 secretion was not altered. Our results define a TNF-dependent cytokine network that favors development of Th1 immune responses.
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PMID:Inhibition of Th1 polarization by soluble TNF receptor is dependent on antigen-presenting cell-derived IL-12. 991 86

Interleukin-12 p70 (IL-12p70) heterodimer, composed of p35 and p40 subunits, is a major Th1-driving cytokine, promoting cell-mediated immunity. In contrast, IL-12p40 homodimer, secreted by APC in the absence of p35 expression, and free p40 monomer do not mediate IL-12 activity but act as IL-12 antagonists. Here it is reported that prostaglandin E(2) (PGE(2)), an inflammatory mediator with a previously known Th2-driving function, dose-dependently enhances the IL-12p40 mRNA expression and the secretion of IL-12p40 protein in human tumor necrosis factor-alpha (TNFalpha)-stimulated immature dendritic cells (DCs). This effect is selective and is not accompanied by the induction of IL-12p35 expression or by secretion of IL-12p70 heterodimer. Inability of TNFalpha/PGE(2) to induce IL-12p70 was not compensated by interferon gamma (IFNgamma), which strongly enhanced the lipopolysaccharide (LPS)-induced IL-12p70 production. In addition to the selective induction of IL-12p40 in TNFalpha-stimulated DCs, PGE(2) inhibited the production of IL-12p70 and IL-12p40 in DCs stimulated with LPS or CD40 ligand. These data suggest an additional level of the Th2-promoting activity of PGE(2), via selective induction of IL-12p40. Selective induction of IL-12p40 and suppression of bioactive IL-12p70 may have negative impact on anticancer vaccination with PGE(2)-matured DCs. (Blood. 2001;97:3466-3469)
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PMID:Prostaglandin E(2) is a selective inducer of interleukin-12 p40 (IL-12p40) production and an inhibitor of bioactive IL-12p70 heterodimer. 1136 38

We have recently demonstrated that dendritic cells (DC) prepared from nonobese diabetic (NOD) mice, a spontaneous model for insulin-dependent diabetes mellitus, exhibit elevated levels of NF-kappaB activation upon stimulation. In the current study, we investigated the influence of dysregulation of NF-kappaB activation on the APC function of bone marrow-derived DC prepared from NOD vs BALB/c and nonobese diabetes-resistant mice. NOD DC pulsed with either peptide or virus were found to be more efficient than BALB/c DC at stimulating in vitro naive Ag-specific CD8+ T cells. The T cell stimulatory capacity of NOD DC was suppressed by gene transfer of a modified form of IkappaBalpha, indicating a direct role for NF-kappaB in this process. Furthermore, neutralization of IL-12(p70) to block autocrine-mediated activation of DC also significantly reduced the capacity of NOD DC to stimulate T cells. Despite a reduction in low molecular mass polypeptide-2 expression relative to BALB/c DC, no effect on proteasome-dependent events associated with the NF-kappaB signaling pathway or Ag processing was detected in NOD DC. Finally, DC from nonobese diabetes-resistant mice, a strain genotypically similar to NOD yet disease resistant, resembled BALB/c and not NOD DC in terms of the level of NF-kappaB activation, secretion of IL-12(p70) and TNF-alpha, and the capacity to stimulate T cells. Therefore, elevated NF-kappaB activation and enhanced APC function are specific for the NOD genotype and correlate with the progression of insulin-dependent diabetes mellitus. These results also provide further evidence indicating a key role for NF-kappaB in regulating the APC function of DC.
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PMID:Elevated NF-kappaB activation in nonobese diabetic mouse dendritic cells results in enhanced APC function. 1175 62

Type 1 diabetes is characterized by a chronic inflammatory response resulting in the selective destruction of the insulin-producing beta cells. We have previously demonstrated that dendritic cells (DCs) prepared from nonobese diabetic (NOD) mice, a model for spontaneous type 1 diabetes, exhibit hyperactivation of NF-kappaB resulting in an increased capacity to secrete proinflammatory cytokines and stimulate T cells compared with DCs of nondiabetic strains of mice. In the current study, the activational status of NF-kappaB and its role in regulating the APC function of macrophages (Mphi) prepared from NOD, nonobese resistant (NOR), and BALB/c mice was investigated. Independent of the stimulus, splenic and bone marrow-derived Mphi prepared from NOD mice exhibited increased NF-kappaB activation relative to NOR and BALB/c Mphi. This hyperactivation was detected for different NF-kappaB complexes and correlated with increased IkappaBalpha degradation. Furthermore, increased NF-kappaB activation resulted in an enhanced capacity of NOD vs NOR or BALB/c Mphi to secrete IL-12(p70), TNF-alpha, and IL-1alpha, which was inhibited upon infection with an adenoviral recombinant encoding a modified form of IkappaBalpha. In contrast, elevated NF-kappaB activation had no significant effect on the capacity of NOD Mphi to stimulate CD4(+) or CD8(+) T cells in an Ag-specific manner. These results demonstrate that in addition to NOD DCs, NOD Mphi exhibit hyperactivation of NF-kappaB, which correlates with an increased ability to mediate a proinflammatory response. Furthermore, NF-kappaB influences Mphi APC function by regulating cytokine secretion but not T cell stimulation.
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PMID:NF-kappa B hyperactivation has differential effects on the APC function of nonobese diabetic mouse macrophages. 1257 41

Stimulation of the APC by Porphyromonas gingivalis LPS has been shown to result in the production of certain pro- and anti-inflammatory cytokines. However, the signaling pathways that regulate these processes are currently unknown. In the present study, the role of the phosphatidylinositol 3 kinase (PI3K)-Akt pathway in regulating P. gingivalis LPS-induced production of IL-10, IL-12 p40, and IL-12 p70 by human monocytes was investigated. P. gingivalis LPS selectively activates the PI3K-Akt pathway via Toll-like receptor 2, and inhibition of this pathway results in an abrogation of extracellular signal-regulated kinase 1/2 phosphorylation, whereas the activation of p38 and c-Jun N-terminal kinase 1/2 kinases were unaffected. Analysis of cytokine production following stimulation of monocytes with P. gingivalis LPS revealed that inhibition of the PI3K pathway differentially regulated IL-10 and IL-12 synthesis. IL-10 production was suppressed, whereas IL-12 levels were enhanced. Inhibition of P. gingivalis LPS-mediated activation of the PI3K-Akt pathway resulted in a pronounced augmentation of NF-kappaB p65 that was independent of IkappaB-alpha degradation. Furthermore, the ability of the PI3K-Akt pathway to modulate IL-10 and IL-12 production appears to be mediated by the selective suppression of extracellular signal-regulated kinase 1/2 activity, as the MEK1 inhibitor PD98059 closely mimicked the effects of wortmannin and LY294002 to differentially regulate IL-10 and IL-12 production by P. gingivalis LPS-stimulated monocytes. These studies provide new insight into how engagement of the PI3K-Akt pathway by P. gingivalis LPS affects the induction of key immunoregulatory cytokines that control both qualitative and quantitative aspects of innate and adaptive immunity.
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PMID:Role of the phosphatidylinositol 3 kinase-Akt pathway in the regulation of IL-10 and IL-12 by Porphyromonas gingivalis lipopolysaccharide. 1284 38

Parasite Ag-specific T cell unresponsiveness and diminished IFN-gamma production are immunologic hallmarks of patent infection with lymph-dwelling filarial nematodes. Although this diminished responsiveness is directed primarily against the intravascular microfilarial (MF) parasite stage and mediated in part by reduced APC function, the mechanisms involved are not fully understood. In this report, we demonstrate that human dendritic cells (DC) exposed to live MF up-regulate both the cell surface and gene expression of CD54 (ICAM-1). Moreover, live MF result in a 3-fold increase in DC death compared with MF-unexposed DC, primarily due to apoptosis. Notably, microarray and real-time RT-PCR data indicate that live MF concurrently up-regulate mRNA expression of proinflammatory molecules such as IL-8, RANTES, IL-1alpha, TNF-alpha, and IL-beta in DC, the presence of which is also detected at the protein level, while inhibiting the production of IL-12 (p40 and p70) and IL-10. Soluble excretory-secretory products from live MF diminished IL-12 and IL-10 production and induced DC death, although to a lesser degree. Moreover, exposure of DC to live MF resulted in a decrease in the ability of DC to promote CD4(+) T cell production of IFN-gamma and IL-5. Our findings clearly suggest that the interaction between live MF and DC is complex but contributes to the hyporesponsiveness and parasite persistence associated with the MF(+) state in the infected human. These data further suggest that MF induce an orchestrated response in APC that leads to a diminished capacity to function appropriately, which in turn has significant consequences for CD4(+) T cells.
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PMID:Brugia malayi microfilariae induce cell death in human dendritic cells, inhibit their ability to make IL-12 and IL-10, and reduce their capacity to activate CD4+ T cells. 1290 98

Co-stimulation via 4-1BB and its ligand 4-1BB ligand (4-1BB-L) plays an important role in cytotoxic and pro-inflammatory immune responses. 4-1BB-L is generally described on activated antigen-presenting cells but there is limited information on its expression and function in human dendritic cells (DC). We herein compared purified CD1a+CD14- DC issued from monocytes or from hematopoietic progenitor cells (HPC). These DC expressed 4-1BB-L mRNA transcripts with highest cell surface levels on HPC-derived DC cultured with IL-1. Pro-inflammatory activation, particularly CD40 ligand+IL-1, up-regulated 4-1BB-L on DC. We confirmed reverse signaling via 4-1BB-L as immobilized 4-1BB in conjunction with CD40-L, enhanced IL-12beta mRNA and the secretion of IL-12 p70 in various APC, including monocytes. Altogether, DC may differ in T cell co-stimulation properties due to variable and regulated levels of 4-1BB-L. Data illustrate reciprocal stimulations between T cells and APC via up-regulated receptor/ligands and production of key cytokines that consolidate cellular immune responses.
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PMID:4-1BB-ligand is regulated on human dendritic cells and induces the production of IL-12. 1474 6


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