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)

We investigated the involvement of mitogen-activated protein kinases (MAPKs) in the maturation of CD83(-) dendritic cells (DC) derived from human blood monocytes. Maturating agents such as LPS and TNF-alpha induced the phosphorylation of members of the three families of MAPK (extracellular signal-regulated kinase l/2, p46/54 c-Jun N-terminal kinase, and p38 MAPK). SB203580, an inhibitor of the p38 MAPK, but not the extracellular signal-regulated kinase l/2 pathway blocker PD98059, inhibited the up-regulation of CD1a, CD40, CD80, CD86, HLA-DR, and the DC maturation marker CD83 induced by LPS and TNF-alpha. In addition, SB203580 inhibited the enhancement of the allostimulatory capacity and partially prevented the down-regulation of FITC-dextran uptake induced by LPS and TNF-alpha. Likewise, SB203580 partially prevented the up-regulation of IL-1alpha, IL-1beta, IL-lRa, and TNF-alpha mRNA upon stimulation with LPS and TNF-alpha, as well as the release of bioactive TNF-alpha induced by LPS. DC maturation induced by the contact sensitizers 2,4-dinitrofluorobenzene and NiSO(4), as seen by the up-regulation of CD80, CD86, and CD83, was also coupled to the phosphorylation of p38 MAPK, and was inhibited by SB203580. The irritants SDS and benzalkonium chloride that do not induce DC maturation did not trigger p38 MAPK phosphorylation. Together, these data indicate that phosphorylation of p38 MAPK is critical for the maturation of immature DC. These results also suggest that p38 MAPK phosphorylation in DC may become useful for the identification of potential skin contact sensitizers.
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PMID:A critical role for p38 mitogen-activated protein kinase in the maturation of human blood-derived dendritic cells induced by lipopolysaccharide, TNF-alpha, and contact sensitizers. 1123 27

Dendritic cells (DCs) are recognized as major players in the regulation of immune responses to a variety of Ags, including bacterial agents. LPS, a Gram-negative bacterial cell wall component, has been shown to fully activate DCs both in vitro and in vivo. LPS-induced DC maturation involves activation of p38, extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinases, and NF-kappaB. Blocking p38 inhibits LPS-induced maturation of DCs. In this study we investigated the role of LPS in the in vitro generation of immature DCs. We report here that in contrast to the observed beneficial effects on DCs, the presence of LPS in monocyte culture retarded the generation of immature DCs. LPS not only impaired the morphology and reduced the yields of the cultured cells, but also inhibited the up-regulation of surface expression of CD1a, costimulatory and adhesion molecules. Furthermore, LPS up-regulated the secretion of IL-1beta, IL-6, IL-8, IL-10, and TNF-alpha; reduced Ag presentation capacity; and inhibited phosphorylation of ERK, but activated p38, leading to a reduced NF-kappaB activity in treated cells. Neutralizing Ab against IL-10, but not other cytokines, partially blocked the effects of LPS. Inhibiting p38 (by inhibitor SB203580) restored the morphology, phenotype, and Ag presentation capacity of LPS-treated cells. SB203580 also inhibited LPS-induced production of IL-1beta, IL-10, and TNF-alpha; enhanced IL-12 production; and recovered the activity of ERK and NF-kappaB. Thus, our study reveals that LPS has dual effects on DCs that are biologically important: activating existing DCs to initiate an immune response, and inhibiting the generation of new DCs to limit such a response.
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PMID:Novel and detrimental effects of lipopolysaccharide on in vitro generation of immature dendritic cells: involvement of mitogen-activated protein kinase p38. 1456 57

Thioredoxin truncated at its carboxy terminal (Trx80) acts as a cytokine that stimulates monocytes and eosinophils. In the present study, Trx80 was shown to induce differentiation of human CD14(+) monocytes into a cell type not described previously, which we designate as Trx80-activated monocytes (TAMs). TAMs resemble immature dendritic cells (iDCs) generated in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 4 (IL-4) in that both these cell populations exhibit increased proportions of CD1a(+) and mannose receptor (MR)(+) cells. However, in contrast to iDCs, TAMs express high proportion of CD14 and lower proportion of CD83 and HLA-DR. Functional assays revealed that, in comparison to iDCs, TAMs 1) exhibit a higher pinocytic capacity; 2) release significantly higher amounts of the proinflammatory cytokines tumor necrosis factor-alpha (TNF alpha), IL-1 beta, and IL-6 and of the anti-inflammatory cytokine IL-10; and 3) induce a significantly lower proliferative response in allogeneic peripheral blood mononuclear cells (PBMCs). Indeed, Trx80 appears to be the first endogenous substance shown to have the capacity on its own to induce IL-10 production by monocytes. Analysis of the mitogen-activated protein (MAP) kinase signaling pathway revealed that Trx80 induces phosphorylation of p38, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). We propose that Trx80 is an early signal in response to danger, and that TAMs may play a major role in triggering innate immune responses.
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PMID:Truncated thioredoxin (Trx80) induces differentiation of human CD14+ monocytes into a novel cell type (TAMs) via activation of the MAP kinases p38, ERK, and JNK. 1549 31

We have previously demonstrated that iC3b is deposited at the dermal-epidermal junction of the skin following ultraviolet (UV) exposure and that it plays a role in UV-induced immunosuppression and antigenic tolerance. In vitro, iC3b differentially regulates monocyte production of interleukin-10 (IL-10) and IL-12. Additionally, iC3b arrests monocytic cell differentiation into CD1c-expressing dendritic cell (DC) precursors. The present study addresses mitogen-activated protein kinase (MAPK) signalling following the cross-linking of CR3 by its ligand iC3b with regard to monocyte differentiation and cytokine regulation. Sheep erythrocytes were coated with IgM alone (EA) or iC3b (EAiC3b) to allow for CR3 cross-linking onto monocytes. EAiC3b increased the phosphorylation (p) of extracellular signal-regulated kinase (ERK) MAPK in fresh human monocyte, particularly in monocyte-derived DC (MDDC) that were differentiated by means of GM-CSF (1000 U/ml) and IL-4 (200 U/ml) for 2 days before iC3b exposure for an additional 24 h (P=0.034, n=3). CD1a expression, induced by GM-CSF and IL-4, was inhibited by iC3b (EAiC3b vs. EA, P=0.012, n=4). Conversely, the inhibition of ERK by the specific inhibitor (PD98059), but not the p-38 inhibitor SB203580, restored CD1a expression (P=0.011, n=4) in iC3b-stimulated MDDC. Concordantly, the inhibition of ERK during iC3b exposure fully reversed the inhibition of IL-12p70 induction in MDDC by 95% (P<0.01, n=4) and decreased IL-10 production. Taken together, our data demonstrate that iC3b interferes with MDDC differentiation and IL-12 and IL-10 production is mediated via an ERK MAPK-dependent mechanism. Thus, ERK MAPK inhibition may represent a therapeutic strategy for preventing monocytic precursor diversion away from DC differentiation when monocytes enter injured tissues in which iC3b is generated, such as UV-exposed skin.
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PMID:Inhibition of monocyte-derived dendritic cell differentiation and interleukin-12 production by complement iC3b via a mitogen-activated protein kinase signalling pathway. 1581 Aug 89

It is highly desirable that immature dendritic cells (DC) used for tolerance induction maintain steady immature state with predominant interleukin (IL)-10 production. In this study, we attempted to develop DC with durable immaturity and other tolerogenic features by using dexamethasone (Dex). We found DC derived from human monocytes in the presence of 10(-7) m Dex were negative for CD1a. Compared with control transduced DC (Ctrl-DC), Dex-DC expressed lower CD40, CD80 and CD86 but equivalent human leucocyte antigen-DR. Both immature Dex- and Ctrl-DC did not express CD83. Nevertheless, upon stimulation of lipopolysaccharide (LPS) or CD40 ligand, the expression of CD40, CD80, CD83 and CD86 was upregulated on Ctrl-DC but not on Dex-DC. The immaturity of Dex-DC was durable following Dex removal. Interestingly, Dex-DC maintained production of large amount of IL-10 and little IL-12 five days after Dex removed. Further study indicated that high-level IL-10 production by Dex-DC was associated with high-level phosphorylation of extracellular signal-regulated kinase (ERK) as blockade of this enzyme markedly attenuated IL-10 production. Furthermore, Dex-DC sustained the capability of high phosphorylation of ERK and IL-10 production 5 days after Dex removal. In addition, Dex-DC had significantly lower activity in stimulating T-cell proliferation. Neutralization of IL-10, to some extent, promoted DC maturation activated by LPS, as well as T-cell stimulatory activity of Dex-DC. The above findings suggest that IL-10-producing Dex-DC with durable immaturity are potentially useful for induction of immune tolerance.
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PMID:Dexamethasone induces IL-10-producing monocyte-derived dendritic cells with durable immaturity. 1609 Nov 24

Langerhans cell histiocytosis (LCH) is a rare disease characterized by tissue infiltration of clusters of CD1a+/CD207+ histiocyte-like cells and a resultant surrounding inflammatory reaction. Because of its morphological similarity to cutaneous Langerhans cells, LCH was formerly named histiocytosis X in 1987. However, its cell lineage appears closely related to myeloid dendritic cells. In 2010, BRAF-V600E was detected in biopsy specimens from the majority of LCH patients. The subsequent observation of extracellular signal-regulated kinase phosphorylation in almost all LCH samples suggested that LCH was a neoplasm provoked by activation of the mitogen-activated protein (MAP) kinase pathway. Therefore, the 2016 Revised Classification by the Histiocyte Society defined LCH as an inflammatory myeloid neoplasm. Although a series of global and domestic clinical trials have improved the prognosis of pediatric LCH patients, no standard therapy with a high level of evidence for adult cases exists. Generally, LCH patients have a favorable prognosis, but delayed diagnosis and intervention may cause severe damage to the involved organs, resulting in a poor quality of life. Here we present recent advances in the pathophysiology and treatment of LCH to enlighten the understanding of this orphan disease.
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PMID:[Pathophysiology and treatment of adult Langerhans cell histiocytosis]. 3316 96

Rosai-Dorfman disease (RDD) is a rare histiocytosis with heterogenous clinical features. In this study, we characterized the histologic and phenotypic features in 33 RDD patients to better define the pathologic diagnosis. Cases included 24 patients with extracutaneous disease ("R" group), and 9 patients with lesions limited to the skin or subcutaneous tissue ("C" group). We identified OCT2 as a novel marker for the monocyte-macrophage phenotype of RDD, expressed in 97% of RDD cases. In contrast, OCT2 expression was seen in 0% of Erdheim-Chester disease cases and 6.7% of Langerhans cell histiocytosis cases. Other markers useful in the diagnosis of RDD included S100 (100%), CD163 (88%), and cyclin D1 (97%). In a subset of cases, RDD showed moderate to strong expression of factor 13a (30%), p16 (64%), and phosphorylated extracellular signal-regulated kinase (45%); RDD was uniformly negative for ZBTB46, CD1a, and langerin. Within the "R group" of RDD, increased expression of factor 13a or phosphorylated extracellular signal-regulated kinase showed a statistically significant association with multifocal disease (P<0.05). Identification of the unique monocyte-macrophage phenotype of RDD with OCT2 expression furthers our understanding of this complex disease and allows for more uniform classification.
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PMID:Rosai-Dorfman Disease Displays a Unique Monocyte-Macrophage Phenotype Characterized by Expression of OCT2. 3317 41