Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As shown by atopy patch tests, atopic dermatitis (AD) is dominated in its acute phase by the development of a specific T(H)2 response after exposure of the skin to common environmental antigens. Relying on our previous data showing that Staphylococcus aureus enterotoxin B (SEB) induced the activation of monocyte-derived dendritic cells (DCs) through Toll-like receptor (TLR)2 and that SEB-pulsed DCs commit allogenic naive T cells into T(H)2, we assessed monocytes sensitivity to SEB and lipopolysaccharide (LPS) in a group of children and adult patients with AD. Monocytes from AD patients (15 adults with mostly severe disease and 15 children with mild to moderate disease) exhibited an activated and tolerant state as supported by (i) secretion of large amounts of IL-6, IL-10, and tumor necrosis factor-alpha even in the absence of stimulation; (ii) their inability to modulate neither HLA-DR and CD54 nor TLR2 and TLR4 expression after in vitro challenge with SEB; (iii) inhibition of IL-12p70 secretion in response to LPS. Interestingly, monocytes from some of the children studied responded to in vitro challenge with LPS, suggesting new hypotheses to explain disease regression. Our data support the notion that monitoring sensitivity of monocytes to bacterial toxins could prove useful to assess disease progression and prognosis in AD.
J Invest Dermatol 2008 Apr
PMID:Age-related differences in sensitivity of peripheral blood monocytes to lipopolysaccharide and Staphylococcus aureus toxin B in atopic dermatitis. 1796 Jan 85

Acute eczema is an inflammatory skin disease characterized by the formation of small intraepidermal blisters, reduction of the adhesion molecule E-cadherin from the keratinocyte surface, and impaired keratinocyte cohesion. Here, we reveal that the disintegrin and metalloprotease ADAM10 is critically involved in regulating E-cadherin cell-surface expression in cultured primary human keratinocytes and in diseased human skin. Proinflammatory cytokines, transforming growth factor-beta, and lipopolysaccharide led to increased release of soluble E-cadherin by activating mitogen-activated protein kinase signaling in cultured keratinocytes. Moreover, these stimuli decreased the amount of pro-ADAM10 and increased the level of the active protease, leading to loss of E-cadherin from the cell surface and decreased keratinocyte cohesion. In situ examination and immunoblot analyses of E-cadherin and ADAM10 expression in lesional skin of eczema revealed that the reduction of E-cadherin expression in areas of blister formation closely correlated with increased level of ADAM10 expression and elevated E-cadherin shedding. Our data suggest that ADAM10-mediated E-cadherin proteolysis leads to the impaired cohesion of keratinocytes observed in eczematous dermatitis and provide previously unreported insights into the understanding of the molecular mechanisms involved in inflammatory diseases with loss in epithelial integrity.
J Invest Dermatol 2008 Jul
PMID:ADAM10-mediated E-cadherin release is regulated by proinflammatory cytokines and modulates keratinocyte cohesion in eczematous dermatitis. 1820 54

Norepinephrine (NE) can modulate dendritic cell (DC) activation in animal models, but the response of human DC to NE and other response modifiers is as yet not completely understood. Here we report the effect of NE on the cytokine response of a mixed population of human DC cells to extracellular stimuli. These cells were obtained by differentiating human cord blood CD34+ precursor cells. NE inhibited the lipopolysaccharide (LPS)-stimulated production of interleukin (IL)-23, IL-12 p40, tumor necrosis factor (TNF)-alpha and IL-6 whereas the expression of IL-10 was not significantly affected. Thus, human cord blood-derived DC respond to NE in a manner similar to mouse Langerhans cells (LC). Furthermore, forskolin also inhibited the LPS-induced levels of TNF-alpha, IL-12 p40, IL-23 p19 and IL-6, supporting the hypothesis that the effects of NE are mediated by cAMP. Data from experiments using inhibitors of adrenergic receptors suggest that NE acts through beta-adrenergic receptors. As IL-23 promotes the differentiation of CD4+ T cells required for T(H)1-mediated immunity, we suggest that NE decreases the differentiation of CD4+ T cells needed for T(H)1-mediated contact hypersensitivity and that NE is a candidate regulator of human DC functions in the skin.
Exp Dermatol 2008 Mar
PMID:Norepinephrine modulates human dendritic cell activation by altering cytokine release. 1820 18

We have observed that lipopolysaccharide (LPS) induces pigmentation in melanocytes and in this study have examined whether these responses are mediated by the p38 mitogen-activated protein kinase (MAPK) signaling pathway. LPS appears to stimulate the pigmentation of melanocytes and cultured skin. LPS was found to induce the expression of microphthalmia-associated transcription factor (MITF) and tyrosinase protein in cells. Stimulation of melanocytes with LPS led to time dependent phosphorylation of p38 MAPK. Furthermore, p38 MAPK functionally regulated the LPS-induced melanin formation in melanocytes; a p38 MAPK inhibitor, SB203580, almost completely attenuated the LPS-mediated up-regulation of melanin synthesis and induction of MITF and tyrosinase expression. These findings indicate that activation of p38 MAPK plays an important role in LPS-induced melanogenesis by up-regulating MITF and tyrosinase expression.
Arch Dermatol Res 2008 Jul
PMID:LPS induces melanogenesis through p38 MAPK activation in human melanocytes. 1847 40

The Toll-like receptors (TLRs) play an important role in the recognition of Candida albicans components and activation of innate immunity. Phospholipomannan (PLM), a glycolipid, is expressed at the surface of C. albicans cell wall, which acts as a member of the pathogen-associated molecular patterns family. In this study, we sought to clarify whether C. albicans-native PLM could induce an inflammation response in human keratinocytes and to determine the underlying mechanisms. Exposure of cultured human primary keratinocytes to PLM led to the increased gene expression and secretion of proinflammatory cytokines (IL-6) and chemokines (IL-8). PLM hydrolysed with beta-d-mannoside mannohydrolase failed to induce gene expression and secretion of IL-6 and IL-8. PLM up-regulated the mRNA and protein levels of TLR2, whereas the mRNA level of TLR4 was not altered. Keratinocytes challenged with PLM resulted in the activation of NF-kappaB and mitogen-activated protein kinase (MAPKs) including p38. Anti-TLR2 neutralizing antibody, NFkappaB and p38MAPK inhibitors blocked the PLM-induced secretion of IL-6, IL-8 in keratinocytes, but no such effect was observed in pretreatment with anti-TLR4-neutralizing antibody and lipopolysaccharide inhibitor (polymyxin B). These data suggest C. albicans-native PLM may contribute to the inflammatory responses of cutaneous candidiasis in the TLR2-NF-kappaB and p38MAPK signalling pathway dependent manner.
Exp Dermatol 2009 Jul
PMID:Candida albicans phospholipomannan triggers inflammatory responses of human keratinocytes through Toll-like receptor 2. 1919 44

Migration of dendritic cells (DCs) from skin to lymph nodes on activation is an essential step in the initiation of an adequate immune response. The dermal microenvironment including stromal cells and their soluble factors might be involved in the regulation of DC migration. To focus on the role of dermal fibroblasts, we studied whether interaction of DCs with fibroblasts promotes the migration of DCs. DCs were co-cultured with resting fibroblasts or with tumor necrosis factor (TNF)alpha/IL-1beta-activated fibroblasts to mimic an inflammatory microenvironment. Interaction of DCs with TNFalpha/IL-1beta-stimulated fibroblasts increased the secretion of matrix metalloproteinase-9 (MMP-9) from DCs within 6 hours compared with DCs alone or DCs stimulated with lipopolysaccharide or TNFalpha/IL-1beta. In contrast, unstimulated fibroblasts did not affect MMP-9 secretion. IL-6 released by TNFalpha/IL-1beta-stimulated fibroblasts was identified as a factor responsible for fibroblast-stimulated MMP-9 secretion from DCs. In accordance with the elevated MMP-9 release, on co-culture with TNFalpha/IL-1beta-stimulated fibroblasts, DCs migrated significantly more effectively through matrigel matrices than did TNFalpha/IL-1beta-stimulated DCs. This was inhibited by a selective blocking of MMP-9, indicating the importance of MMP-9 for this migratory capacity of DCs. In summary, fibroblasts in the local dermal microenvironment are capable of potentiating the migratory capacity of DCs, and thus have the potential to actively participate in the regulation of a cutaneous immune response.
J Invest Dermatol 2010 Feb
PMID:Dermal fibroblasts promote the migration of dendritic cells. 1971 Jun 90

Thioredoxin-1 is a ubiquitous protein involved in phenotypical and functional changes in dendritic cells (DC). We investigated the effect of lipopolysaccharide (LPS), skin sensitizers, and irritants on thioredoxin-1 by Western blot and immunofluorescence and on mRNA by real-time PCR. As DC models, we used a skin DC line and DC derived from human blood monocytes. We observed that all tested chemicals increased thioredoxin-1 expression, which is only transient for irritants, being the strongest effect observed for LPS (63 +/- 15%). To address the involvement of thioredoxin-1 in DC maturation, we analysed the effect of an activator of thioredoxin-1 expression, hydrogen peroxide, on CD86 expression, a marker of DC maturation. We found that hydrogen peroxide increases thioredoxin-1 and CD86 expression reinforcing thioredoxin-1 involvement in DC maturation. Because mitogen-activated protein kinases and PI3K are activated upon DC maturation, we also analysed their involvement in thioredoxin-1 modulation. We verified that LPS-induced upregulation of thioredoxin-1 expression was dependent on PI3K pathway.
Arch Dermatol Res 2010 May
PMID:Effect of lipopolysaccharide, skin sensitizers and irritants on thioredoxin-1 expression in dendritic cells: relevance of different signalling pathways. 1975 73

Regulatory T cells (Treg) have been found to be central for host defense regulation against microbial antigens, the prevention of allergic and autoimmune diseases and the suppression of effective tumor immune responses. However, the influence of the microenvironment and the mechanisms leading to their activation in the periphery still remain unclear. In vitro infection models revealed that survival and suppressive function of Treg is improved when they are confronted with lipopolysaccharide (LPS). Because LPS initiates signalling via the receptor Toll-like receptor 4 (TLR4) and the consequent activation of the transcription factor nuclear factor-kappaB (NF-kappaB), we investigated TLR4 expression and NF-kappaB regulation in human Treg. We demonstrated that LPS in combination with IL-2 induces human CD25(+)FoxP3(+) T cells in vitro. FoxP3 expression of purified natural Treg increased and suppressive capacity was markedly improved compared with unstimulated Treg upon stimulation with LPS/IL-2. Furthermore, blockade of the NF-kappaB pathway by a selective inhibitor of IkappaB kinase (IKK)beta abrogated the upregulation of FoxP3 expression. Taken together, our results suggest an important role of the NF-kappaB signalling pathway for the induction and modulation of suppressive function of natural Treg, if they are confronted with TLR4-stimulating agents such as Gram-negative bacteria.
Exp Dermatol 2010 Jan
PMID:The NF-kappaB signalling pathway is involved in the LPS/IL-2-induced upregulation of FoxP3 expression in human CD4+CD25high regulatory T cells. 1984 58

The diarylheptanoid, oregonin (ORE), which was isolated from the bark of Alnus japonica Steudel that grows natively in Korea, has been known to exert antioxidative, anti-inflammatory, anti-cancer and immune response inhibitory effects. The antioxidative effect of ORE was observed on the superoxide and 1,1-diphenyl-2-picrylhydrazyl radical, as well as on the expression of inducible nitric oxide synthase and cyclooxygenase-2 in lipopolysaccharide-treated RAW264.7 macrophages. The statistically significant inhibitory action of ORE against production of cytokines induced by bacterial products or by interleukin (IL)-1beta, free radicals and nitrogen species, and a corresponding increase in cellular calcium concentration because of ORE were confirmed in bone marrow and spleen dendritic cells that are known to play important functions in the development and advancement of atopic dermatitis (AD). It was thus expected that ORE would exert a beneficial effect in the treatment of AD. A study on the pharmaceutical benefits of ORE against AD has not yet been conducted in vivo. We therefore used an in vivo AD animal model, namely the NC/Nga mice, and by applying ORE onto the animals through skin application as well as intraperitoneal injection, we attempted to evaluate the benefits of ORE in this system. Evaluation of ORE was conducted by following the SCORE method to score the effect, as well as by measuring the Th2 cytokines IL-4, IL-5 and IL-13 levels from serum and lymphocytes, and IgE and eosinophil levels from serum. Additionally, the expression of mRNA and protein levels was estimated using real-time polymerase chain reaction and Western blotting analysis. The following categories of clinical evaluation, Th2 cytokines IL-4, IL-5 and IL-13 values, serum IgE levels, serum eosinophil levels, and mRNA and protein expression levels of iNOS and COX-2, were evaluated from topical application and intraperitoneal injection groups of ORE. The effects of ORE on AD in NC/Nga mice were confirmed as being similar to the positive control group, while a significant difference with the negative control group was observed. The results presented in this report suggest that ORE might be beneficial in the treatment of AD.
Exp Dermatol 2010 Aug
PMID:Effect of topical application and intraperitoneal injection of oregonin on atopic dermatitis in NC/Nga mice. 1984 16

Thalidomide is anti-inflammatory under some conditions, yet has been reported to up-regulate Th1 (T helper 1) immunity measured by increased IL-2 (Interleukin-2) and gamma interferon. The authors have assessed the effect of thalidomide and analogues, di- and tri-thiothalidomide, on a lipopolysaccharide (LPS) activated macrophage cell line (RAW 246.7 cells). The authors' findings showed that nitric oxide (NO) was significantly inhibited by thalidomide (15%) and its analogues (di-thiothalidomide; 15%, tri-thiothalidomide; 32%). The proinflammatory molecules TNF-alpha (tumor necrosis factor-alpha) and IL-6 were not significantly inhibited. Pretreatment with thalidomide and analogues before activation was not different from simultaneous treatment. Inhibition of inducible nitric oxide synthase (iNOS) may prove to be an important target for the anti-inflammatory and anti-cancer effects of thalidomide and related immunomodulatory drugs (IMiDs).
J Drugs Dermatol 2010 Apr
PMID:Effect of thalidomide on nitric oxide production in lipopolysaccharide-activated RAW 264.7 cells. 2051 89


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