Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The intracellular inositol pathway is an important route for cell activation and relies on the stimulation of membrane-bound phosphoinositide-specific phospholipase C (PLC). Previously we have shown abnormalities of inositol metabolism in mononuclear cells (MNL) in atopic dermatitis (AD) using an indirect method. We now describe a direct method of measuring PLC activity in membrane and cytosol preparations of MNL in AD. We compare PLC activity in AD with that in normal controls and examine the effect of substrate concentration and nucleotide stimulation on the system. Our findings show increased membrane-bound PLC activity in AD compared with normal controls. Non-specific stimulation of AD PLC activity by nucleotides suggests that the enzyme of atopics is more sensitive to substrate-driven activity than that of non-atopics.
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PMID:Measurement of phosphoinositide-specific phospholipase C activity in mononuclear leucocytes from atopic and normal subjects. 139 Jan 61

It has been proposed that toxins and other bacterial protein products of Staphylococcus aureus can act as triggers or persistence factors in several inflammatory skin diseases. In this study, we examined the S. aureus isolates from the skin of patients with atopic dermatitis and psoriasis. We found that the bacterial isolates from these patients exhibited either characteristic superantigenic toxins or thermolabile toxins believed to be staphylococcal alpha-toxin. All of these staphylococcal strains also secreted extracellular staphylococcal protein A. We found significant differences in the action of these toxins on human keratinocytes and keratinocyte cell lines. The superantigenic toxins toxic shock syndrome toxin-1, staphylococcal enterotoxins A and B, and exfoliative toxin-A, as well as staphylococcal protein A, did not induce significant cytotoxic damage in the keratinocyte cell line HaCaT, whereas the staphylococcal alpha-toxin produced profound cytotoxicity. Keratinocyte cytotoxicity induced by staphylococcal alpha-toxin was time and concentration dependent and demonstrated the morphologic and functional characteristics of necrosis, not apoptosis. Addition of alpha-toxin to keratinocytes simultaneously induced cell lysis and tumor necrosis factor-alpha release into the medium within 30 min; apparently, it was constitutive tumor necrosis factor-alpha. On the other hand, superantigenic toxins and, in particular, protein A showed stimulation of tumor necrosis factor-alpha secretion in keratinocytes and release of this cytokine after 6-12 h of incubation. Thus, staphylococcal protein A, alpha-toxin, and superantigenic toxins found in S. aureus isolates from patients with psoriasis and atopic dermatitis can produce direct pro-inflammatory effects on keratinocytes through the release of tumor necrosis factor-alpha. We propose that these effects may be relevant to the induction and persistence of lesions in these two diseases.
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PMID:Staphylococcal toxins and protein A differentially induce cytotoxicity and release of tumor necrosis factor-alpha from human keratinocytes. 882 68

We studied the relationship between cAMP and house dust mite-induced cytokine production in T cells from mite-sensitive patients with atopic dermatitis. T cells from atopic dermatitis patients secreted high level of interleukin-13 (mean 851.1 pg per ml) when cultured with autologous monocytes pulsed with Dermatophagoides pteronyssinus extract. Dermato- phagoides pteronyssinus-induced interleukin-13 secretion was not detected in normal subjects. Adenylate cyclase inhibitor MDL 12,330A and cyclic nucleotide phosphodiesterase type 4 inhibitor rolipram blocked Dermatophagoides pteronyssinus-induced interleukin-13 secretion in atopic dermatitis T cells. In atopic dermatitis T cells, cAMP level rose at 5 min after Dermatophagoides pteronyssinus stimulus then decreased to the basal level at 1 h. MDL 12,330A blocked the Dermatophagoides pteronyssinus-induced cAMP elevation while rolipram blocked its reversal. In atopic dermatitis T cells, adenylate cyclase activity increased at 5 min after Dermatophagoides pteronyssinus stimulus, followed by the increase of cyclic nucleotide phosphodiesterase activity at 15 min. In atopic dermatitis T cells, phospholipase C inhibitor ET-18-OCH3 blocked Dermatophagoides pteronyssinus-induced activation of adenylate cyclase, while rolipram, protein kinase A inhibitor H-89, and MDL 12,330A blocked the activation of cyclic nucleotide phosphodiesterase. These results suggest that Dermatophagoides pteronyssinus may first increase cAMP in atopic dermatitis T cells by activating adenylate cyclase via phospholipase C, and next decrease cAMP by activating cyclic nucleotide phosphodiesterase 4 via protein kinase A, which may be activated by adenylate cyclase-generated cAMP signal. These events are required for interleukin-13 response Dermatophagoides pteronyssinus.
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PMID:Intracellular 3',5'-adenosine cyclic monophosphate level regulates house dust mite-induced interleukin-13 production by T cells from mite-sensitive patients with atopic dermatitis. 1116 92

Skin infections with Staphylococcus aureus are not only an important cause of morbidity and even mortality, but are thought to serve as initiation and/or persistance factors for numerous inflammatory skin diseases, including psoriasis and atopic dermatitis. One mechanism by which S. aureus can modulate the immune system is through the production of proteins such as superantigenic toxins, Protein A, as well through the cytolytic alpha-toxin. This review serves to discuss the biology of these three types of proteins, with emphasis on their ability to stimulate the production of powerful pro-inflammatory lipid- and protein-derived cytokines in keratinocytes. Characterization of interactions between these proteins and the keratinocyte can provide a better understanding of how bacterial infection modulates inflammatory skin diseases, as well as provide the basis for improved therapies involving antibacterial agents.
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PMID:The keratinocyte as a target for staphylococcal bacterial toxins. 1192 32

The trimeric high-affinity IgE receptor (FcepsilonRI) on human epidermal Langerhans cells mediates IgE-dependent antigen uptake and subsequent antigen focusing. Its expression is upregulated on Langerhans cells (FcepsilonRIhigh Langerhans cells) and inflammatory dendritic epidermal cells (FcepsilonRIhigh inflammatory dendritic epidermal cells) in the skin of patients with atopic dermatitis. In the absence of the amplifying beta-chain in these cells, FcepsilonRI signaling (indicated by calcium mobilization and activation of the transcription factor nuclear factor-kappaB) is only detectable in FcepsilonRIhigh Langerhans cells from atopics, but not FcepsilonRIlow Langerhans cells from nonatopics. Therefore we investigated protein-tyrosine kinases putatively involved in FcepsilonRI signaling in Langerhans cells and asked whether differences in their expression and FcepsilonRI-induced activity could explain the dichotomic responses observed in atopic vs nonatopic individuals. First, we found the src protein-tyrosine kinases p53/56lyn, p59fyn, p56/59hck, p55c-fgr, and p60c-src to be expressed in Langerhans cells from all donors. In addition, whereas p56lck was lacking, p72syk and the negative regulatory p50csk were detected. Upon terminal maturation of Langerhans cells in vitro, no significant change of the protein- tyrosine kinase expression profile except downregulation of p56/59hck was observed. In contrast, significant upregulation of all protein-tyrosine kinase expressed except p50csk was detected in FcepsilonRIhigh Langerhans cells, but not in FcepsilonRIhigh inflammatory dendritic epidermal cells. Finally, the important protein-tyrosine kinases substrate phospholipase C-gamma1, which is also essential for downstream calcium mobilization, was only phosphorylated upon FcepsilonRI triggering in FcepsilonRIhigh Langerhans cells from atopics, but not in FcepsilonRIlow Langerhans cells from nonatopics. Therefore, upregulation of FcepsilonRI and protein-tyrosine kinase expression as well as subsequent protein-tyrosine kinase activity may explain, at least in part, that an efficient signaling pathway in terms of calcium mobilization is restricted to FcepsilonRIhigh Langerhans cells from atopic individuals. Key words:
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PMID:Enhanced expression and activity of protein-tyrosine kinases establishes a functional signaling pathway only in FcepsilonRIhigh Langerhans cells from atopic individuals. 1240 24

Atopic dermatitis is characterized by increased skin innervation. The expression of neurotrophin-4 is enhanced in the epidermal keratinocytes of lesions with atopic dermatitis and may be related to hyperinnervation in these lesions. Prostaglandin E(2) (PGE(2)) levels are increased in lesions with atopic dermatitis; thus, PGE(2) may be involved in the development of this disease. We examined the in vitro effects of PGE(2) on neurotrophin-4 production in human keratinocytes. PGE(2) and EP1/EP3 agonist sulprostone increased neurotrophin-4 secretion and mRNA levels without altering its mRNA stability. Antisense Sp1 oligodeoxynucleotide and Sp1 inhibitor mithramycin A suppressed PGE(2) and sulprostone-induced neurotrophin-4 expression, indicating the requirement for Sp1 for expression. PGE(2) or sulprostone markedly enhanced the phosphorylation, DNA binding, and transcriptional activity of Sp1 and modestly increased Sp1 mRNA and protein levels. PGE(2) or sulprostone induced the membrane translocation of protein kinase Calpha and the phosphorylation of extracellular signal-regulated kinase (ERK). PGE(2)-induced increases in neurotrophin-4 expression, Sp1 transcriptional and DNA-binding activity, Sp1 mRNA and protein levels, and ERK phosphorylation were suppressed by antisense EP3 oligodeoxynucleotide, inhibitors of phosphatidylinositol-specific phospholipase C, conventional protein kinase C, and mitogen-activated protein kinase/ERK kinase 1 (MEK1). These results suggest that PGE(2) enhances neurotrophin-4 production by activating Sp1 via the EP3/phosphatidylinositol-specific phospholipase C/protein kinase Calpha/MEK1/ERK pathway. PGE(2) may promote innervation in skin lesions with atopic dermatitis via the induction of neurotrophin-4.
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PMID:Prostaglandin E2 enhances neurotrophin-4 production via EP3 receptor in human keratinocytes. 1608 78

Sphingosine-1-phosphate (S1P), a bioactive sphingolipid metabolite, regulates multiple cellular responses such as Ca(2+) signaling, growth, survival, and differentiation. Because sphingosine kinase (SphK) is the enzyme directly responsible for production of S1P, many factors have been identified that regulate its activity and subsequent S1P levels. Here we synthesized a previously unidentified SphK activator, K6PC-5, and have studied its effects on intracellular Ca(2+) signaling in HaCaT cells and epidermal differentiation in murine skin. K6PC-5, a hydrophobic compound chemically named N-(1,3-dihydroxyisopropyl)-2-hexyl-3-oxo-decanamide, activated SphK (obtained from C57BL/6 murine blood and F9-12 cell lysates) in a dose-dependent manner. K6PC-5 induced both intracellular Ca(2+) concentration ([Ca(2+)](i)) oscillations in HaCaT cells and Ca(2+) mobilization in hairless mouse epidermis. Both dimethylsphingosine (DMS) and dihydroxysphingosine (DHS), SphK inhibitors, and transfection of SphK1-siRNA blocked K6PC-5-induced increases in [Ca(2+)](i). The K6PC-5-induced [Ca(2+)](i) oscillations were dependent on thapsigargin-sensitive Ca(2+) stores and Ca(2+) entry, but independent of the classical phospholipase C-mediated pathway. In addition, K6PC-5 enhanced the expression of involucrin and filaggrin, specific differentiation-associated marker proteins in HaCaT cells, whereas transfection of SphK1-siRNA blocked the increase of involucrin. Topical K6PC-5 also enhanced the expression of involucrin, loricrin, filaggrin, and keratin 5 in intact murine epidermis. Finally, topical K6PC-5 inhibited epidermal hyperplasia by exerting antiproliferative effects on keratinocytes in murine epidermis. These results suggest that K6PC-5 acts to regulate both differentiation and proliferation of keratinocytes via [Ca(2+)](i) responses through S1P production. Thus, regulation of S1P levels may represent a novel approach for treatment of skin disorders characterized by abnormal differentiation and proliferation, such as atopic dermatitis and psoriasis.
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PMID:K6PC-5, a direct activator of sphingosine kinase 1, promotes epidermal differentiation through intracellular Ca2+ signaling. 1838 62

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) strains have emerged as serious health threats in the last 15 years. They are associated with large numbers of atopic dermatitis skin and soft tissue infections, but when they originate from skin and mucous membranes, have the capacity to produce sepsis and highly fatal pulmonary infections characterized as necrotizing pneumonia, purpura fulminans, and postviral toxic shock syndrome. This review is a discussion of the emergence of 3 major CA-MRSA organisms, designated CA-MRSA USA400, followed by USA300, and most recently USA200. CA-MRSA USA300 and USA400 isolates and their methicillin-sensitive counterparts (community-associated methicillin-sensitive S aureus) typically produce highly inflammatory cytolysins alpha-toxin, gamma-toxin, delta-toxin (as representative of the phenol soluble modulin family of cytolysins), and Panton Valentine leukocidin. USA300 isolates produce the superantigens enterotoxin-like Q and a highly pyrogenic deletion variant of toxic shock syndrome toxin 1 (TSST-1), whereas USA400 isolates produce the superantigens staphylococcal enterotoxin B or staphylococcal enterotoxin C. USA200 CA-MRSA isolates produce small amounts of cytolysins but produce high levels of TSST-1. In contrast, their methicillin-sensitive S aureus counterparts produce various cytolysins, apparently in part dependent on the niche occupied in the host and levels of TSST-1 expressed. Significant differences seen in production of secreted virulence factors by CA-MRSA versus hospital-associated methicillin-resistant S aureus and community-associated methicillin-sensitive S aureus strains appear to be a result of the need to specialize as the result of energy drains from both virulence factor production and methicillin resistance.
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PMID:Secreted virulence factor comparison between methicillin-resistant and methicillin-sensitive Staphylococcus aureus, and its relevance to atopic dermatitis. 2010 35

Patients with atopic dermatitis (AD) are frequently colonized with Staphylococcus aureus, with one-third of isolates producing alpha-toxin. Moreover, S. aureus colonization is positively correlated with the severity of eczema. Interleukin-17A (IL-17A) has gained attention in diseases associated with chronic skin infections. The aim of this study was to investigate the effects of sublytic alpha-toxin concentrations on IL-17A production. Sublytic alpha-toxin concentrations strongly induced IL-17A in peripheral blood mononuclear cells (PBMCs), isolated CD4(+) T cells, polarized Th17 cells, and Th17 clones from reactive atopy patch test lesions and blood from AD patients. Alpha-toxin induced IL-17A directly in T cells. The effect of alpha-toxin was further amplified by upregulation of IL-1 in monocytes. In conclusion, higher levels of IL-17A secretion induced by alpha-toxin in the skin partially explain how colonization with S. aureus can contribute to chronic skin inflammation.
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PMID:Staphylococcal alpha-toxin is a strong inducer of interleukin-17 in humans. 2124 72

Allergic diseases accompanied by skin inflammation are intricately regulated by several mediators. Among these molecules, neurotransmitters are known to affect several immune cells such as T cells, B cells, dendritic cells, and mast cells. Neurotransmitters are released from nerve endings, and most of them work through specific G-protein coupled receptors. In this review, we discuss the interactions of representative neurotransmitters, calcitonin gene-related peptide (CGRP), substance P (SP), neuropeptide Y (NPY), vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating polypeptide (PACAP), and prostaglandins (PGs), as well as their receptor signaling systems such as the cAMP/protein kinase A (PKA) pathway, phospholipase C (PLC) activation, and calcium ion channel activation, in cutaneous immunity. Although many studies have proposed that these neurotransmitters play several roles in mouse contact hypersensitivity (CHS) models, human allergic contact dermatitis (ACD), and atopic dermatitis (AD), their physiological effects are controversial due to the diverse and complex mechanisms of skin inflammation. Both Th1- and Th2-mediated skin inflammation are well known, and neurotransmitters affect the kinds of inflammatory cells and subsequent immune reactions in them. In addition, the characteristics of antigen-presenting cells are also different in Th1- or Th2-mediated immune responses. Therefore, we take particular note of the type of skin inflammation, Th1- or Th2-mediated, and review the physiological roles of the neurotransmitters in skin inflammation.
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PMID:Neuronal derivative mediators that regulate cutaneous inflammations. 2323 7


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