Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate whether growth factors derived from T cells in psoriatic lesions are able to stimulate keratinocyte growth, T-cell lines were initiated from lesional psoriasis skin and cloned by limiting dilution. Eight clones with good proliferative capacity out of 40 clones from one patient were stimulated. After 24 h, the conditioned medium was harvested and the growth modulatory effect of the conditioned medium on keratinocytes was assessed. Seven of the eight T-cell clones stimulated keratinocyte growth to an extent ranging from 22% +/- 19 to 64% +/- 9 (mean +/- SD of three experiments) of maximal inducible keratinocyte growth, and one T-cell clone had no effect (-5% +/- 2) on keratinocyte growth. Keratinocyte growth was also induced by T-cell clones obtained from two other patients. Several cytokines were tested in this system to determine which T-cell growth factor may induce the keratinocyte growth. None of the cytokines interferon-g, transforming growth factor-beta, interleukin (IL)-2, IL-3, IL-4, IL-6, IL-8, or granulocyte-macrophage colony stimulating factor alone was found to possibly be responsible for the T-cell-induced keratinocyte growth. Thus the nature of the T-cell keratinocyte growth-promoting stimulus remains to be elucidated.
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PMID:T-lymphocyte clones initiated from lesional psoriatic skin release growth factors that induce keratinocyte proliferation. 822 31

To better understand the cellular target(s) of cyclosporin action in psoriasis, we have studied the effects of systemic short-term (7 d), low-dose (3-7.5 mg/kg) cyclosporin A administration on the expression of the cytokines interleukin (IL)-8 and IL-1 beta in psoriatic lesions. RNA blot hybridization analysis of pretreatment keratome biopsies revealed that expression of both cytokine mRNAs was highly variable from patient to patient. Significant covariation of both cytokine mRNA levels was noted (r = 0.86, p < 0.0001). However, there was no significant correlation between expression of either cytokine and clinical severity, as measured by the pretreatment Psoriasis Area and Severity Index (PASI). IL-1 beta protein levels measured by enzyme-linked immunosorbent assay (ELISA) were highly correlated with IL-1 beta mRNA levels, indicating that the differences in transcript levels accurately reflect differences in epidermal cytokine protein. Significant reductions in both cytokine transcripts and in IL-1 beta immunoreactive protein were noted in the high expression subgroup after 1 week of cyclosporin A therapy, prior to detectable clinical improvement. In contrast to its pronounced effects on epidermal cytokine expression in vivo and the allogeneic mixed lymphocyte reaction in vitro, cyclosporine A did not inhibit the induction of intercellular adhesion molecule (ICAM)-1 or IL-8 mRNAs by cultured keratinocytes in response to IL-1 beta or the combination of tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma. These data suggest that epidermal keratinocytes respond to signals produced by activated T cells by coordinate expression of multiple cytokines, and that cyclosporin A acts primarily through blockade of T cells, rather than through keratinocyte activation.
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PMID:Cyclosporin A rapidly inhibits epidermal cytokine expression in psoriasis lesions, but not in cytokine-stimulated cultured keratinocytes. 824 2

Interleukin (IL)-8 and gro peptides are members of the intercrine-alpha family of chemotaxins known to be present in biologically active form in psoriasis lesions. However, the relative contribution of the three different gro genes to the expression of this material is unknown, as is the stimulus for gro overexpression in psoriatic lesions. To address these questions, Northern blot and semiquantitative polymerase chain reaction analysis were performed on RNA extracted from keratome biopsies of normal skin, untreated plaques of psoriasis, or plaques treated for 1 week with low-dose cyclosporin A (CsA). Northern blot analysis revealed a significant correlation between gro and IL-8 mRNA levels in psoriasis lesions from 26 different individuals (r = 0.61, p = 0.0009), and overexpression of gro was markedly reduced by CsA prior to detectable clinical improvement (79.3%, p = 0.01, n = 22). To determine which form(s) of gro were overexpressed in psoriatic lesions, total keratome RNA (1 microgram) was analyzed by semiquantitative reverse transcription-polymerase chain reaction (SQRT-PCR). In five patients known to markedly overexpress gro and IL-8 mRNAs by Northern blotting, gro-alpha was approximately six times more abundant than gro-beta, and 25 times more abundant than gro-gamma. In cultured human keratinocytes, all three forms of gro mRNA were increased by IL-1 alpha or by interferon (IFN)-gamma plus tumor necrosis factor (TNF)-alpha. However, in contrast to the situation in vivo, CsA had no inhibitory effect on cytokine-stimulated gro expression in cultured keratinocytes. Taken together, these results demonstrate that the gro-alpha gene is selectively overexpressed in psoriatic lesions and strongly suggest that overexpression of gro is a keratinocyte response to activated T cells in psoriasis.
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PMID:GRO-alpha mRNA is selectively overexpressed in psoriatic epidermis and is reduced by cyclosporin A in vivo, but not in cultured keratinocytes. 824 3

Topical steroid treatment is a common therapy for psoriasis. Steroids are known to bind to specific cytoplasmic receptors and to influence gene expression. We investigated the effects of the novel steroid derivative mometasone furoate on the expression of putative target genes in normal human epidermal cells (KC). Gene expression was measured by semiquantitative mRNA-PCR. In addition, cytokine receptor characteristics were assessed by ligand binding studies. We found a dose-dependent downregulation of proinflammatory mediators (IL-8, TNF alpha). Genes involved in growth regulation (HER-2, p53) were also modulated. IL-8 binding to KC was inhibited. We conclude that modulation of the expression of cytokine, cytokine receptor and growth factor genes may contribute to the antipsoriatic action of steroids.
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PMID:Novel steroid derivative modulates gene expression of cytokines and growth regulators. 852 52

Interleukin(IL-)6 is overproduced in psoriatic lesions. We investigated the contribution of dermal fibroblasts to the local IL-6 production. Fibroblasts (passageno. 2 to 6) derived from lesional psoriatic (PP) and normal human (NN) skin were used to analyse the secretion of IL-6, and the related cytokines IL-1, IL-8 and TNF-alpha, and the expression of their corresponding mRNA by bioassay, ELISA and Northern hybridization, respectively. PP fibroblasts cultured under serum-free conditions produced increased amounts of bioactive IL-6 when compared to NN fibroblasts. Differences were partially restored in the presence of growth factors or serum. The serum-induced IL-6 production reached a maximum within 24 h after seeding and remained unchanged in PP fibroblasts, whereas comparable amounts of IL-6 were produced only 6 days later in NN fibroblasts. There was a clear expression of IL-6 mRNA in both types of fibroblasts under serum-free conditions. Unexpectedly, fetal calf serum, inactivated fetal calf serum as well as human serum completely inhibited the expression of IL-6 mRNA in all the PP fibroblast cultures investigated. NN fibroblasts were clearly less sensitive to this inhibiting effect of serum. Furthermore, medium supplemented with serum-free component or calcium also repressed IL-6 mRNA expression in PP fibroblasts in contrast to NN fibroblasts. Cycloheximide fully restored the repressing effect of serum indicating that serum induced a labile repressor protein. PP and NN fibroblasts produced negligible amounts of IL-1 and TNF-alpha, but the production of IL-8, however, was comparable to that of IL-6. Our results show a differently regulated IL-6 synthesis in PP fibroblasts in vitro, suggesting an active contribution of dermal fibroblasts to the local IL-6 production in psoriasis.
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PMID:Expression of cytokines and their receptors by psoriatic fibroblast. I. Altered IL-6 synthesis. 874 69

There is ample evidence that several cytokines, including transforming growth factor-alpha (TGF-alpha), interleukin (IL)-6, and IL-8 are upregulated in psoriasis, suggesting a pathogenic role for these cytokines. The sequence of these events, however, has not been elucidated. Recently it has been reported that TGF-alpha induces IL-6 in thymocytes through posttranscriptional regulation; therefore, we were interested in whether TGF-alpha can also induce IL-6 in human keratinocytes. Thus, we stimulated the human keratinocyte cell line HaCaT with TGF-alpha and tested supernatants for IL-6 activity. TGF-alpha resulted in a significant induction of the release of IL-6. This was also confirmed by northern blot analysis, which revealed a transient increase in IL-6 mRNA. This increase was unlikely due to enhanced mRNA stability, because we could not observe induction of IL-6 -specific transcripts by TGF-alpha in the presence of actinomycin D. To determine whether IL-6 induction by TGF-alpha is transcriptionally regulated, we transfected fragments of the IL-6 upstream region, subcloned into a plasmid just upstream of the chloramphenicol acetyl transferase coding region, into HaCaT cells. A 238-bp fragment and a 123-bp fragment, both containing nuclear factor (NF)-IL-6 and NFkappaB sites, exhibited significant induction of chloramphenicol acetyl transferase activity upon treatment with TGF-alpha. Because IL-6 transcription is known to be regulated by activation of NFkappaB and NF-IL-6, we analyzed the activation of these DNA-binding proteins by electrophoretic mobility shift assays. NF-IL-6 binding to a 32P-labeled NF-IL-6 binding sequence was enhanced 20 min after TGF-alpha stimulation and returned to basal levels within 90 min, whereas NFkappaB binding activity was enhanced after 20 min and returned to normal 60 min after stimulation. We conclude that TGF-alpha induces IL-6 in HaCaT cells and, in contrast to thymocytes, may do so by transcriptional activation, possibly through activation of NFkappaB and NF-IL-6.
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PMID:Transforming growth factor-alpha induces interleukin-6 in the human keratinocyte cell line HaCaT mainly by transcriptional activation. 875 56

IL-8 is a potent neutrophil attractant and activator. IL-8 has been reported to be involved in the pathogenesis of several diseases, including rheumatoid arthritis, sepsis, psoriasis, and the adult respiratory distress syndrome (ARDS). Our previous studies demonstrated that high concentrations of IL-8 were present in alveolar fluids from patients with ARDS and were associated with increased mortality. In this study we report that a major portion of IL-8 in bronchoalveolar fluids from patients with ARDS is associated with anti-IL-8 autoantibody (anti-IL-8:IL-8 complexes). Free autoantibodies that recognize IL-8 were also detected in these fluids. Next, we examined the properties of anti-IL-8 autoantibodies present in lung fluids from ARDS patients and compared them with autoantibodies from normal plasma and arthritic synovial fluids. The anti-IL-8 autoantibody was polyclonal, and IgG3 and IgG4 were the primary IgG subclasses. Anti-IL-8:IL-8 complexes consisted of one IgG and one IL-8 molecule. In addition, anti-IL-8 autoantibody bound IL-8 with a high affinity (approximately 10(-12) M) and inhibited IL-8 interaction with its specific receptors on neutrophils. The results suggest that anti-IL-8 autoantibodies may regulate IL-8 activity.
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PMID:Anti-IL-8 autoantibodies in alveolar fluid from patients with the adult respiratory distress syndrome. 880 76

Interleukin-8 (IL-8) may be important in psoriasis as it is expressed in the stratum granulosum, attracts polymorphonuclear cells, and stimulates angiogenesis and keratinocyte mitogenesis. To study intrinsic cutaneous factors in psoriasis, we constructed skin equivalents from psoriatic or adult control fibroblasts with normal foreskin keratinocytes. IL-8 levels were measured in supernatants by enzyme-linked immunosorbent assay and in skin equivalents by immunohistochemistry and in situ hybridization. IL-8 was highly induced in skin equivalents compared to cells grown alone. Epidermal stratification varied among fibroblast lines and was correlated with IL-8 levels, but lesional and nonlesional psoriatic skin equivalents from the same donor were similar. Six fibroblast lines (two psoriasis lesion and four normal) supported only monolayers, while 12 lines (seven psoriasis lesion and five normal) produced stratification. Mean IL-8 levels were significantly lower in dermal equivalents of the first group than the second (0.78 +/- 0.40 vs 3.93 +/- 2.83 ng per ml, mean +/- SD, p = 0.01, analysis of variance). Significantly more IL-8 was secreted by psoriatic than normal fibroblast skin equivalents over 14 d (p = 0.015) with greatest differences at 1 and 4 d. Psoriatic IL-8 levels peaked first and remained increased. IL-8 protein and mRNA were initially strongest in dermal fibroblasts, and at the dermal-epidermal interface. Diffuse epidermal expression was replaced by accentuation in the stratum granulosum. Psoriatic skin equivalents were thicker, had more intense IL-8 staining, and developed invagination. We hypothesize that an IL-8 paracrine loop between fibroblasts and keratinocytes may play a key role in epidermal regeneration in the skin equivalent, in normal wound healing, and in the determination of an intrinsic psoriatic wound-healing phenotype.
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PMID:Interleukin-8 is induced in skin equivalents and is highest in those derived from psoriatic fibroblasts. 882 70

To determine whether an improvement in skin lesions as a result of PUVA therapy may be correlated with changes in cytokine patterns, RT-PCR amplification was used to compare the levels of IL-2, IL-6, IL-8, IL-10, TNF-alpha and IFN-gamma cytokine mRNA expression in serial biopsies from three chronic plaque psoriatic patients. In each case, 3-mm punch biopsies were taken from lesional skin before and during 2-28 days of treatment with PUVA. Total mRNA was extracted from each biopsy, cDNA synthesized, and then amplified by 35 cycles of PCR using cytokine-specific primers. The specificity of the PCR products was confirmed by the Southern blot technique. Substantial levels of specific mRNA for each of the cytokines studied was present in the lesions prior to treatment. In two of the three patients who responded well to PUVA, a reduction in all the cytokines including IL-10 was observed compared with baseline levels. In contrast, PUVA proved to be ineffective in clearing the psoriasis of the third patient whose skin lesions worsened during the course of treatment. This was accompanied by an increase in IFN-gamma but not of the other cytokines investigated, above the pretreatment level. This study showed an association between PUVA-induced resolution and decreases in the levels of various cytokines highly expressed in psoriatic lesions.
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PMID:Cytokine expression in psoriatic skin lesions during PUVA therapy. 884 18

The CD40/gp39 pathway is known to be an important feature of B/T cell collaboration leading to T cell-dependent activation, proliferation or differentiation of B cells. Additionally, CD40 is involved in the regulation of B cell survival and apoptosis. Recently, CD40 has been shown to be expressed functionally on non-hematopoietic cells, i.e. endothelial cells. Here, we demonstrate that human keratinocytes (KC) cultured in vitro express CD40 constitutively. The surface expression of CD40 is markedly up-regulated following stimulation with interferon (IFN)-gamma, but not with tumor necrosis factor-alpha or interleukin (IL)-1 beta. This process is regulated at the CD40 mRNA level as demonstrated by Northern blot analysis. Furthermore, ligation of CD40 via soluble gp39, the CD40 ligand, enhances intercellular adhesion molecule (ICAM)-1 and Bcl-x up-regulation on IFN-gamma-stimulated KC, but not lymphocyte function-associated antigen (LFA)-3, B7-2, HLA-DR, or Fas expression. The release of IL-8 is also induced following CD40 ligation on KC. In psoriasis, a T cell-mediated inflammatory skin disease, KC have a markedly enhanced expression of CD40. This expression co-localizes with the expression of ICAM-1, Bcl-x, and an influx of CD3+ T cells. These findings suggest a functional role of CD40 on KC in inflammatory skin disorders such as psoriasis and could make a therapeutic intervention by disrupting the CD40/gp39 pathway an approach to consider in these inflammatory skin diseases.
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PMID:CD40 is functionally expressed on human keratinocytes. 889 41


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