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 (0.01 seconds)

In response to exogenous stimuli such as phorbol-12-myristate 13-acetate, ultraviolet B radiation, and lipopolysaccharide, human keratinocytes produce soluble mediators that are important in primary contact irritancy including cytokines that are associated with proinflammatory properties (interleukin-1 alpha [IL-1 alpha], tumor necrosis factor alpha), chemotaxis (IL-8), and growth activation (granulocyte/macrophage colony stimulating factor, IL-6, transforming growth factor alpha). We examined qualitative and quantitative changes in selected intracellular and secreted cytokines in human keratinocyte cultures in response to non-sensitizing contact irritants (croton oil, sodium lauryl sulfate, methyl salicylate, ethyl phenylpropiolate), sensitizing irritants (oxazolone, dinitrofluorobenzene), and ulcerative agents (phenol, benzalkonium chloride, chromium trioxide). The chemicals were also applied to mouse skin to assess whether the chemical-specific pattern of inflammation correlated with the in vitro production of keratinocyte-derived cytokines. Although all agents elicited neutrophils to the site of chemical application, time dependent and chemical-specific patterns of inflammation could be detected. Sodium lauryl sulfate, phenol, and croton oil induced increases in IL-8 production at non-cytotoxic concentrations in semi-confluent human keratinocyte cultures. Phenol and croton oil stimulated tumor necrosis factor alpha production, whereas croton oil was the only agent found to induce granulocyte/macrophage colony-stimulating factor production. Croton oil, phenol, benzalkonium chloride, and dinitrofluorobenzene induced the intracellular production of IL-1 alpha without a concomitant release into the medium. The release of cytokines occurred in parallel with a relative increase in cytokine-specific mRNA transcripts. Studies using neutralizing antibodies to tumor necrosis factor alpha and IL-1 alpha demonstrated that IL-8 induction by croton oil and phenol occurred directly rather than through autocrine circuits. These data suggest that a given pattern of cytokine production is chemical-specific and may predict the contribution of keratinocytes to skin inflammation.
J Invest Dermatol 1994 Jun
PMID:Cytokine induction in human epidermal keratinocytes exposed to contact irritants and its relation to chemical-induced inflammation in mouse skin. 800 54

ETH615 (4-(2-quinolylmethoxy)-N-(3-fluorobenzyl-phenyl-amino-methyl -4- benzoic-acid), a synthetic inhibitor of leukotriene B4 production and activities, was tested for its effect on the production of and biological responses towards human interleukin-8. We found that ETH615 inhibits lipopolysaccharide-induced (LPS-induced) expression of interleukin-8 messenger-RNA (mRNA) and interleukin-8 production in human peripheral blood mononuclear cells. We also observed that ETH615 completely inhibited interleukin-8 as well as leukotriene B4 directed chemotaxis of human neutrophils in a dose-dependent manner. A moderate effect on fMLP-directed neutrophil chemotaxis was observed. Further, no significant effect on either interleukin-8, leukotriene B4 or fMLP-directed T-cell migration was observed. These results further support the concept of a cytokine-leukotriene regulatory circuit and encourage the establishment of clinical trials testing the effect of ETH615 on inflammatory skin diseases, which are characterized by high levels of interleukin-8 and leukotriene B4 in lesional skin.
Exp Dermatol 1993 Aug
PMID:ETH615, a synthetic inhibitor of leukotriene biosynthesis and function, also inhibits the production of and biological responses towards interleukin-8. 816 35

Pro-inflammatory cytokines mediate their biological functions after they are secreted or released from intracellular to extracellular milieu. Keratinocytes have proven to be able to produce various cytokines including IL-1 and IL-8. Dysregulations of IL-1 and IL-8 were found in psoriatic lesions. Recently, vitamin D3 (VD3) was found to be an effective and safe therapy for psoriasis. In the present study, we investigated the effects of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and its analogue MC903 on IL-1 alpha and IL-8 secretion by human keratinocytes in vitro. Cultured normal human keratinocytes (NHKs) produced considerable amounts of IL-1 alpha but secreted less. In contrast, they produced less IL-8 and almost all molecules were secreted to the culture supernatants. Treatment of unstimulated NHKs with 1,25(OH)2D3 or MC903 showed little effects on IL-1 alpha production and secretion though they slightly enhanced IL-8. When NHKs were stimulated with tumour necrosis factor-alpha (TNF alpha), both IL-1 alpha and IL-8 secretions were enhanced and these enhancements were inhibited by 1,25(OH)2D3 or MC903. Stimulation of NHKs with phorbol 12-myristate 13-acetate(PMA) and lipopolysaccharide(LPS) resulted in an increase of IL-8 and decrease of IL-1 alpha in the culture supernatants. Addition of 1,25(OH)2D3 or MC903 inhibited the increased secretion of IL-8 but restored decreased secretion of IL-1 alpha from stimulated NHKs dose dependently. Hydrocortisone and cyclosporin A showed similar inhibitory effects on PMA/LPS-increased IL-8 secretion from NHKs but had little effect of restoring IL-1 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)
J Dermatol Sci 1994 Feb
PMID:Regulatory effects of 1,25-dihydroxyvitamin D3 and a novel vitamin D3 analogue MC903 on secretion of interleukin-1 alpha (IL-1 alpha) and IL-8 by normal human keratinocytes and a human squamous cell carcinoma cell line (HSC-1). 819 81

A newly defined clinical syndrome, haemorrhagic cellulitis, is described in 12 patients. The syndrome consists of an acute onset of extremely painful erythema affecting dependent areas, followed by dermal haemorrhage and sloughing of the overlying epidermis, and requiring both antibiotics and systemic corticosteroids for complete resolution. The patients usually have demonstrable Gram-negative or Gram-positive infection, of non-cutaneous origin, and underlying systemic disease. Vacuolopathic necrosis of epidermal keratinocytes, and damaged vascular endothelium of the dermal blood vessels can be demonstrated by light and electron microscopy, as well as by lectin studies. Immunocytochemical studies reveal the presence of activated macrophages and T lymphocytes. We believe the syndrome is due to lipopolysaccharide-induced or bacterial mitogen-induced tumour necrosis factor-alpha (TNF-alpha), secreted by previously primed activated macrophages in a second-set response. TNF-alpha characteristically injures endothelial cells and epidermal keratinocytes. It is thought to induce its cytotoxic effects partly via neutrophil degranulation, and partly via DNAase activation, with resultant DNA fragmentation and cell lysis. Corticosteroids have been shown not only to inhibit TNF-alpha secretion by activated macrophages, but also to block its cytotoxicity, thus accounting for the extremely rapid clinical response to this drug in conjunction with adequate and appropriate antibiotic therapy.
Br J Dermatol 1994 Jan
PMID:Haemorrhagic cellulitis: a syndrome associated with tumour necrosis factor-alpha. 830 20

Fibrin deposition is an important histopathological feature of inflammatory skin lesions and is mediated in part, by procoagulants generated by mononuclear leucocytes (MNL). We examined whether MNL from patients with atopic dermatitis or psoriasis generate enhanced procoagulant activity (PCA). MNL isolated from the peripheral blood of 15 healthy control individuals, 15 patients with atopic dermatitis and 15 patients with psoriasis were incubated for 24 h in the presence or absence of bacterial lipopolysaccharide (LPS). MNL or the cell culture supernatants were then added to recalcified human plasma to determine the clotting time. We found that in both atopic dermatitis and psoriasis MNL cultured in the presence or absence of LPS expressed greatly enhanced PCA (p < 0.01 to < 0.002). Supernatants from MNL cultures from patients with psoriasis, but not those from patients with atopic dermatitis, also generated augmented PCA (p < 0.002). In psoriasis, PCA normalized after successful topical treatment with anthralin. We conclude that enhanced PCA is a characteristic feature of MNL in both atopic dermatitis and psoriasis. In psoriasis the enhanced PCA is directly related to disease activity.
Arch Dermatol Res 1993
PMID:Enhanced procoagulant activity of mononuclear leukocytes in patients with atopic dermatitis and psoriasis. 837 92

The neutrophil-activating peptide 1/interleukin 8 (NAP-1/IL-8) has in the past been extensively characterized biochemically as well as functionally. Effects of NAP-1/IL-8 on inflammatory cells like neutrophilic granulocytes and lymphocytes, as well as its production by several different cell types, point towards an important role in different inflammatory processes. Recently, monoclonal antibodies have helped to establish immunoassays for detecting the peptide. Using such antibodies, we have performed in vitro studies on the time- and stimulus-dependent production of IL-8 by endothelial cells as well as fibroblasts. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 alpha (IL-1 alpha) efficiently induced both focal intracellular expression as well as secretion of the peptide when tested by immunocytochemistry and enzyme-linked immunosorbent assay (ELISA). After stimulation with phorbol myristate acetate (PMA) and lipopolysaccharide (LPS), such effects were seen only in endothelial cells, whereas interferon (IFN)-gamma did not induce any pronounced effect on either of the cells tested. These studies demonstrated in vitro release of IL-8 by different cells upon specific stimulation, thus underlining the significance of the in vivo secretion of this peptide, as noted in recent studies.
J Invest Dermatol 1993 Oct
PMID:Time- and stimulus-dependent secretion of NAP-1/IL-8 by human fibroblasts and endothelial cells. 840 26

PN-E2 is a monoclonal antibody generated against recombinant tumor necrosis factor-alpha (TNF-alpha)-treated human umbilical vein endothelial cells (EC). PN-E2 recognized a molecule with expression levels in vitro that could be downregulated by TNF, and in situ PN-E2 showed only weak reactivity with vascular EC in normal skin, as assessed by immunohistochemical staining. The expression of PN-E2 was considerably increased on EC in various pathologic skin lesions, including psoriasis, granulation tissue, and inflamed skin. PN-E2 antigen expression was analyzed in more detail in vitro on cultured EC and fibroblasts by use of enzyme-linked immunosorbent assay and fluorescence-activated cell sorter techniques. The expression level on human umbilical vein endothelial cells and capillary EC was, in contrast to the in situ immunohistologic findings, invariably high. On fibroblasts, a low expression was found. Incubation of the EC with recombinant TNF-alpha decreased expression by a factor of 2. Incubation of EC with recombinant interferon-gamma resulted in a twofold increase in PN-E2 antigen expression, whereas other cytokines [recombinant interleukin (rIL)-1 alpha, rIL-1 beta, rIL-4, rIL-6], lipopolysaccharide, or recombinant basic fibroblast growth factor had no effect. Immunoelectron microscopy of tissue specimens and EC preparations localized the antigen on the luminal membrane of the endothelium. Immunoprecipitation followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis revealed a major band at 90 kDa and a minor band at 80 kDa under reducing conditions and bands of 180 and 400 kDa under non-reducing conditions. Molecular weight and expression patterns in vitro on EC after incubation with cytokines excluded most of the known endothelium-specific molecules, with the possible exception of endoglin (the 44G4 antigen). We conclude from our findings that this new antigen could be useful as a marker for endothelial activation in skin biopsy material.
J Invest Dermatol 1993 Jan
PMID:A new 180-kDa dermal endothelial cell activation antigen: in vitro and in situ characteristics. 842 88

Nitric oxide (NO) is produced by a variety of human and animal cells and is involved in a broad array of physiological and pathophysiological processes. It can cause vasodilation, serve as a neurotransmitter, and have anti-neoplastic, anti-microbial, and anti-proliferative effects. In this study, we have demonstrated that fibroblasts derived from human skin spontaneously produce NO and that this production can be enhanced by stimulating the cells with interferon-gamma and lipopolysaccharide. The production of NO by human dermal fibroblasts can be blocked by NG-monomethyl-L-arginine (L-NMMA). The inhibitory effect of L-NMMA on NO production was restored by addition of L-arginine but not D-arginine. By measuring the rate of conversion of [14C]L-arginine to [14C]L-citrulline, we show that unstimulated cells expressed only Ca2+-dependent NO synthase (NOS) activity (1.36 +/- 0.57 pmol/mg/min; n = 4) whereas stimulated cells expressed both Ca2+-dependent (2.60 +/- 0.54 pmol/mg/min; n = 4) and -independent (1.59 +/- 0.14 pmol/mg/min; n = 4) NOS activities. With reverse transcription polymerase chain reaction (RT-PCR), the 422-bp RT-PCR product for human endothelial constitutive NOS and the 462-bp RT-PCR product for human hepatocyte inducible NOS were detected in proportion to the amount of mRNA-related RT-cDNA added to the reaction mixture. Further evidence by immunocytochemistry demonstrated that human dermal fibroblasts express both constitutive and inducible NOS proteins. These data collectively suggest that in addition to macrophages and other inflammatory cells, nitric oxide production by dermal fibroblasts could be important during the inflammatory stages of wound healing and possibly also in the later stages of proliferation and tissue remodeling after skin injury in humans.
J Invest Dermatol 1996 Mar
PMID:Human dermal fibroblasts produce nitric oxide and express both constitutive and inducible nitric oxide synthase isoforms. 864 70

The importance of nitric oxide (NO) in mediating macrophage functions has been demonstrated, but production of this potent gas has not been examined in Langerhans cells (LC). Using murine LC purified from epidermal cell suspensions and the recently established LC-like cell line derived from newborn BALB/c epidermis (XS-52), it was shown with reverse transcriptase (RT)-PCR that inducible nitric oxide synthase (iNOS) message is present in these cells. Murine keratinocytes did not contain iNOS message. iNOS mRNA was increased in a concentration-dependent manner by lipopolysaccharide (LPS) in purified murine LC and XS-52 cells, and immunofluorescence using an antibody to iNOS revealed bright cytoplasmic staining in LPS-treated XS-52 cells. Anti-iNOS antibody brightly stained LC on human neonatal foreskin cryosections. An increase in NO production by LPS-treated XS-52 cells over 16 h, as measured by the determination of nitrite levels in culture supernatants using the Griess Reaction, was observed. Interferon-gamma (IFNgamma) did not affect NO production on its own. In the presence of LPS and IFNgamma, NO production was 3 times more than observed with LPS alone. NO production was inhibited by the NOS inhibitor L-NAME. Western blots with anti-iNOS antibody demonstrated an increase in iNOS expression in LPS-treated XS-52 cells that was suppressed by IL-10. NO produced in LC may affect LC functions such as microbicidal activity, antigen presentation, and cytotoxicity and may affect adjacent keratinocytes and melanocytes.
J Invest Dermatol 1996 Dec
PMID:Langerhans cells express inducible nitric oxide synthase and produce nitric oxide. 894 67

Our laboratory has recently developed the monoclonal antibody 4F7 which recognizes a molecule on dendritic cells in the dermis of mice that is upregulated after application of contact allergens in vivo. Furthermore, this antibody detects an antigen on dendritic cells in spleen, lymph nodes and colon. In order to study the influence of contact allergens on the surface expression of the 4F7 molecules on dendritic cells, FACScan analysis of splenic dendritic cells was carried out after in vitro application of contact allergens. Freshly isolated splenic dendritic cells were found to be positive for 4F7, 33D1, N418 (CD11c) and MHC class II. After overnight culture the expression of the dendritic cell-specific molecules 4F7 and 33D1 was decreased. This downregulation was not inhibited by the addition of the cytokines TNF-alpha or GM-CSF during in vitro culture. However, in vitro treatment of freshly isolated dendritic cells with the contact allergen 2,4-dinitrofluorobenzene prevented this downregulation of the 4F7 surface molecules. The same effect was observed after treatment with other contact allergens (1-chloro-2,4-dinitrobenzene or potassium dichromate). Treatment with the irritant substance sodium dodecyl sulphate, the lectins concanavalin and lipopolysaccharide or the phorbol ester PMA did not prevent the downregulation of 4F7 and 33D1. Moreover, the influence of contact allergens on the expression of the molecules 4F7 and 33D1 was not inhibited by the protein synthesis inhibitor cycloheximide. No effects of contact sensitizers were detectable on the expression of MHC class II molecules or the costimulatory molecules B7 and heat-stable antigen. Our results show a specific stabilizing effect of contact allergens on the dendritic cell-specific molecules 4F7 and 33D1 independent of de novo protein synthesis.
Arch Dermatol Res 1996 Nov
PMID:Specific stabilization of the 4F7 molecule on dendritic cells by contact allergens. 895 Apr 54


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