Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Why is it that primary melanomas which are less than 0.76 mm in thickness are almost always curable by surgery whereas thicker lesions are associated with a worse prognosis? Put in another way, why is it that such small increases in tumor thickness beyond 0.76 mm are often associated with the eventual formation of distant metastases and death? Part of the answer lies in the dramatic qualitative changes which can accompany small increases in the size of primary human melanomas. Thus, primary melanomas less than 0.76 mm in thickness usually contain very low proportions of metastatically competent tumor cells, whereas slightly thicker lesions can contain very high proportions of such cells, resulting from a selective growth advantage of the latter in the dermal mesenchyme. This overgrowth process is akin to a 'malignant eclipse' phenomenon (by analogy with a solar eclipse). We have been studying the causes of the malignant eclipse in melanoma, for which there are at least four possibilities: 1) an increase in autocrine, mitogenic growth factors by melanoma cells; 2) a decreased rate of apoptosis in the same population; 3) an acquired resistance to paracrine growth inhibitory factors; and 4) an increased ability to induce an angiogenic response. Evidence exists for all four possibilities. Our experimental approach to studying this problem has relied heavily on the use of cell lines obtained from early stage radial growth phase or vertical growth phase lesions which have a clinical-like inability to grow progressively in nude mice, and variants obtained from such lines which are aggressively tumorigenic. Using such paired lines, and other experimental systems, we have obtained evidence that shows early stage melanoma cell lines may be deficient in inducing angiogenesis, are highly sensitive to the growth inhibitory effects of a plethora of cytokines, including transforming growth factor beta, interleukin-6, and oncostatin M, and are more sensitive to undergoing spontaneous apoptosis in several conditions including when growth in anchor-age-independent, 3-dimensional tissue culture. How this information may impact tumor prognosis and the design and effects of new strategies to treat melanoma, especially antiangiogenesis strategies, is discussed.
J Investig Dermatol Symp Proc 1996 Apr
PMID:Analysis and significance of the malignant 'eclipse' during the progression of primary cutaneous human melanomas. 962 14

Cyclosporine A is a powerful immunosuppressive agent which is widely used for the prevention of allograft rejection and for the treatment of autoimmune diseases. Clinical and experimental data show that it may also act on connective tissue. We investigated the influence of cyclosporine A on granulation tissue formation and wound healing. Using an in vitro approach, we followed the time course of rat dermal fibroblasts during wound repair. Granulation fibroblasts were compared to dermal fibroblasts flow cytometrically and by mRNA analysis with respect to the expression of procollagen alpha1(I), integrin beta1, interleukin-6, transforming growth factor beta1, keratinocyte growth factor and activin betaA. The most pronounced effect in cyclosporine-treated rats was the strong down-regulation of activin beta expression. In cryo-sections of granulation tissue from the same rats, the distribution and expression intensity of intercellular adhesion molecule and its receptors were investigated by immunohistology. Clearly, a time course was detectable. Tissue from CsA-treated animals showed a delay of three days compared to untreated animals. Apoptosis was also delayed in CsA-treated rats by around three days. Furthermore, we investigated the effect of CsA on the expression of collagen alpha1(I), fibronectin and matrix metalloprotease 1 genes in dermal fibroblasts from untreated donors. No changes in the mRNA steady state levels of these genes were revealed after direct addition of different doses of CsA to fibroblast cultures. Our data suggest that CsA may interfere with the complicated net of interactions between connective tissue and the immune system by down-regulation of the inflammatory phase by modulation of cytokines and a subsequent delay of tissue repair.
Eur J Dermatol 1998 Mar
PMID:Cyclosporine A delays wound healing and apoptosis and suppresses activin beta-A expression in rats. 964 3

It has been recently hypothesized that superantigens, which stimulate T cells expressing particular T cell receptor Vbeta chain gene segments, play a precipitating or aggravating role in psoriasis. In this study, we investigated the peripheral blood mononuclear cell (PBMC) response of patients with psoriasis vulgaris to staphylococcal superantigens (staphylococcal enterotoxin A (SEA), SEB, and SEC1) and its relationship to clinical and laboratory findings. Cytokine secretion was assessed by ELISA in the supernatants of the cultured PBMCs stimulated with SEB. Results of 3H-TdR uptake showed that the PBMCs' response against SEB in patients with psoriasis vulgaris (34,468 +/- 6,455) (mean DPM SD) was significantly higher than that of normal subjects (22,756 +/- 5,780) (p < 0.005). The stimulation index (SI) of patients with psoriasis vulgaris (n = 37) (63.9 +/- 55) was significantly higher than that of normal subjects (n = 24) (26.0 +/- 23) (p < 0.005) and patients with atopic dermatitis (n = 10) (40.7 +/- 30) (p < 0.05). Similar results were obtained in response to SEA and SEC1. SI weakly correlated with the psoriasis area and severity index (PASI) score (r = 0.62) and the serum interleukin-6 (IL-6) concentration (r = 0.45). IL-2 and tumor necrosis factor (TNF-alpha) were secreted at a significantly increased level by PBMCs from psoriatic patients on incubation with SEB, after a 3 day culture period. A higher level of IL-6 was released by PBMCs stimulated with SEB in psoriatic patients than normal controls, however, the difference was not significant. These results raise the possibility that monocytes, as well as T cells, are markedly activated by staphylococcal superantigen in patients with psoriasis vulgaris, which may play a role in the triggering or aggravating of psoriasis mediated by secreted cytokines.
Eur J Dermatol
PMID:Clinical analysis of staphylococcal superantigen hyper-reactive patients with psoriasis vulgaris. 968 64

The sunburn reaction is the most common consequence of human exposure to ultraviolet radiation (UVR), and is mediated at least in part by interleukin-6 (IL-6). The aim of this study was to determine if DNA is a major chromophore involved in the induction of IL-6 following UV irradiation of a human epidermoid carcinoma cell line (KB), and of normal human epidermal keratinocytes. We first confirmed that IL-6 release was associated with enhanced levels of IL-6 mRNA transcripts. The wavelength dependence for IL-6 release was then investigated by irradiating the cells at defined wavelengths (254, 302, 313, 334, and 365 nm) with a monochromator. The maximum effect on IL-6 release was observed at 254 nm with only low levels of induction observed at wavelengths above 313 nm. The wavelength dependence for UV-induced IL-6 release was similar to that for DNA absorption or for the induction of cyclobutane pyrimidine dimers (CPD). To determine whether UV-induced DNA damage mediated IL-6 secretion, the role of CPD was investigated by treating keratinocytes with photosomes (photolyase encapsulated in liposomes) followed by photoreactivating light. This photoreversal procedure led to a reduction in the levels of the UVC-induced secretion of IL-6, which in normal human keratinocytes was unambiguously associated with repair of CPD. We conclude that the release of IL-6 from human keratinocytes following short-wave UVC and UVB irradiation is mediated by DNA damage and that CPD play an important role in this process.
J Invest Dermatol 1998 Sep
PMID:Induction of interleukin-6 production by ultraviolet radiation in normal human epidermal keratinocytes and in a human keratinocyte cell line is mediated by DNA damage. 974 Feb 23

Ultraviolet B radiation not only inflicts tumor-initiating DNA damage, but also impairs T cell-mediated immunity relevant to survival of the initiated cells. We have reported, however, that ultraviolet A radiation, in contrast, is immunologically innocuous in hairless mice and opossums, but renders the animals resistant to the immunosuppression by ultraviolet B, or its mediator cis-urocanic acid. Ultraviolet B irradiation of skin causes abundant release of numerous cytokines (interleukin-1, interleukin-6, interleukin-10, tumor necrosis factor-alpha); notably interleukin-12 and interferon-gamma do not appear to be upregulated. A recent report has indicated that interleukin-12 protects from photoimmunosuppression in mice, but it remains unclear whether interleukin-12 acts directly or via interferon-gamma, which it is known to stimulate. Here we investigate the possible role of interferon-gamma in UVA photoimmunoprotection, using interferon-gamma gene knockout mice in comparison with control C57/BL6 mice, and the systemic contact hypersensitivity reaction (induced by sensitization through a nonirradiated skin site) to measure immunity. interferon-gamma-/- mice raised normal contact hypersensitivity responses, and were unaffected, as were C57BL control mice, by ultraviolet A exposure. In response to ultraviolet B irradiation or topical cis-urocanic acid treatment, control mice became immunosuppressed by 69% and 27%, respectively, and interferon-gamma-/- mice by 79% and 27%. When ultraviolet B exposure or cis-urocanic acid was followed by ultraviolet A irradiation, however, contact hypersensitivity was totally restored in control mice, but remained suppressed by 55% and 25%, respectively, in interferon-gamma-/- mice. Injection of recombinant interferon-gamma in the interferon-gamma-/- mice restored the ultraviolet A protective effect against cis-urocanic acid-induced immunosuppression. These observations suggest that interferon-gamma plays a part in ultraviolet A immunoprotection from the suppressive effect of ultraviolet B radiation and, and that the mechanism appears to be via antagonism by this cytokine of the cis-urocanic acid immunosuppressive action.
J Invest Dermatol 1999 Jun
PMID:Interferon-gamma is involved in photoimmunoprotection by UVA (320-400 nm) radiation in mice. 1038 43

Artificial human skin, Skin2 (keratinocytes and fibroblasts) and EpiDerm (keratinocytes), was used to determine heat-induced release/accumulation of mediators of injury and repair. Skin2 was exposed to 37 or 41-45 degrees C for 90 min, followed by 37 degrees C for 22.5 h. Media were analyzed for interleukin-1alpha (IL-1alpha), prostaglandin-E2 (PGE2), thromboxane-B2 (TxB2) and nuclear matrix apparatus protein (NMAP, viability). Specimens were taken for microscopy. Media and lysates from Skin2 and EpiDerm (37 and 45 degrees C) were analyzed for IL-1alpha, its soluble receptor (sIL-1RII), receptor antagonist (IL-1Ra), interleukin-6 (IL-6) and heat shock protein-70A (lysates only). Significant release of IL-1alpha and PGE2 was detected only above 43 degrees C, where viability deteriorated and histological damage (especially to keratinocytes) was observed. With both skin products, sIL-1RII release was heat-depressed. IL-1alpha and IL-1Ra were elevated in media and IL-1Ra appeared to lower the bioactivity of IL-1alpha. Heat depressed IL-6 release from Skin2 fibroblasts. IL-6 production and release were negligible with EpiDerm. Heat increased Hsp-70A in both products. We conclude keratinocytes and fibroblasts are not primary cytokine and prostaglandin sources in heatstroke (< 44 degrees C) but could be in evaporative cooling failure, focal hot spots, or systemic responses. Levels of IL-1Ra, PGE2 and Hsp70A may be important markers of cell status.
J Dermatol Sci 1999 Jul
PMID:Artificial human skin: cytokine, prostaglandin, Hsp70 and histological responses to heat exposure. 1039 88

Activator protein-2 is an important transcription factor for the activation of a number of genes. Here we report the induction of activator protein-2 in response to inflammatory cytokines such as interleukin-6 in keratinocytes. Immunoblotting and semiquantitative reverse transcriptase-polymerase chain reaction assays using normal human keratinocytes revealed that interleukin-6 caused a time- and concentration-dependent induction of activator protein-2 mRNA and protein. The increase of activator protein-2 mRNA was detected at 30 min after stimulation and that of activator protein-2 protein was at 2 h. Their levels were lower than the control levels at 24 h. The interleukin-6-dependent induction of activator protein-2 mRNA was completely blocked by adding actinomycin D, whereas it was approximately 50% affected by cycloheximide. Co-incubation with neutralizing antibodies against various inflammatory cytokines resulted in inhibition of the interleukin-6-dependent activator protein-2 induction at varying degrees, indicating an involvement of various cytokines in the activator protein-2 induction. The activator protein-2 induction was observed in keratinocytes derived from lesional skins with psoriasis or squamous cell carcinoma, and the high levels of activator protein-2 were histochemically detected in these lesions. Furthermore, a gel mobility shift assay using the nuclear extracts from interleukin-6-treated cells showed that interleukin-6 induced the functional activator protein-2 protein for the gene activation. These findings suggest a possible regulation mechanism of activator protein-2 through a complex cytokine system, which is conceivably the initial reaction leading to skin inflammation, and resultant keratinocyte growth and carcinogenesis.
J Invest Dermatol 1999 Oct
PMID:Induction of transcription factor AP-2 by inflammatory cytokines in human keratinocytes. 1050 47

Altered function of the fibroblasts is thought to contribute to the pathogenesis of psoriasis. To further elucidate this point, we compared the ability of fibroblasts from psoriatic lesions and of fibroblasts from healthy individuals to produce interleukin-6 (IL-6). The IL-6 levels were measured by ELISA in serum-free culture medium before and after stimulation of monolayer fibroblasts with various concentrations of tumour necrosis factor-alpha (TNF-alpha), platelet-derived growth factor (PDGF), and interferon-gamma (IFN-gamma), alone and in different combinations. The production of IL-6 in the fibroblast cultures was stimulated by TNF-alpha (0.01-10 nm/ml medium) in a dose-dependent way. Fibroblasts from psoriatic lesions produced lower amounts of IL-6 than fibroblasts from healthy individuals both before and after stimulation with the different concentrations of TNF-alpha (P = 0.012). The ratios between the IL-6 concentrations before and after stimulation with TNF-alpha were similar in both types of fibroblasts, indicating that the capacity to produce IL-6 is reduced in psoriatic fibroblasts compared with healthy ones. The production of IL-6 was not influenced by either PDGF or IFN-gamma. These findings support the view that the phenotype of the fibroblast is altered in psoriasis.
Arch Dermatol Res 1999 Oct
PMID:Psoriatic fibroblasts secrete lower amounts of IL-6 than healthy fibroblasts before and after stimulation with TNF-alpha. 1055 11

The complement system plays an important part in host defense and inflammation. Locally synthesized complement may perform these functions at tissue and organ level. In skin the keratinocyte is the major cell type, it is known to produce two soluble complement components, C3 and factor B. In this study we investigated the regulation of synthesis of these components in foreskin keratinocytes by cytokines. Human keratinocytes were cultured in the presence of supernatant of activated peripheral blood mononuclear cells, interleukin-1alpha, interleukin-2, interleukin-6, transforming growth factor-beta1, tumor necrosis factor-alpha, or interferon-gamma. C3 and factor B proteins were measured in culture supernatant by enzyme-linked immunosorbent assay and C3 and factor B transcripts in harvested cells by reverse transcriptase-polymerase chain reaction. Cultured keratinocytes constitutively produced C3 and factor B. Supernatant of activated mononuclear cells upregulated C3 and factor B production by 27- and 15-fold, respectively. interleukin-1alpha, interferon-gamma, and tumor necrosis factor-alpha upregulated C3 synthesis by 7-, 8-, and 22-fold, and interleukin-1alpha, interleukin-6, and interferon-gamma upregulated factor B synthesis by 3-, 3-, and 34-fold, respectively. Tumor necrosis factor-alpha induced production of C3 and interferon-gamma induced production of factor B were inhibited by cycloheximide. Cytokine induced upregulation of C3 and factor B proteins was always associated with the upregulation of levels of C3 and factor B mRNA. This indicated that, as expected, cytokine-induced enhancement in C3 and factor B levels was due to an increase in synthesis rather than their possible release from intracellular stores. In conclusion, synthesis of C3 and factor B in keratinocytes is regulated by some cytokines, known to be produced by inflammatory cells and keratinocytes.
J Invest Dermatol 2000 Jan
PMID:Synthesis of complement components C3 and factor B in human keratinocytes is differentially regulated by cytokines. 1062 Jan 19

Interleukin-6 (IL-6) is a cytokine implicated as a key mediator of immune and inflammatory responses in psoriasis. Recent studies have shown that neuropeptides, substance P (SP) and vasoactive intestinal peptide (VIP), can modulate a production of IL-6 from cells, such as monocytes and astrocytes, participating in an immune reaction. The aim of this study was to assess the role of the neuropeptides on cytokine production of keratinocytes in physiologic or pathologic conditions. Cultured human keratinocytes derived from normal foreskin and psoriatic lesions were treated with various concentrations of SP or VIP, in the presence or absence of fetal bovine serum. The secretion of IL-6 by the treated keratinocytes was analyzed by enzyme-linked immunosorbent assay. Although neither SP nor VIP, by itself, was able to induce IL-6 synthesis in cultured human keratinocytes, we have found that SP, not VIP, significantly reduced 5% fetal bovine serum-induced IL-6 production in time- and dose-dependent fashion. This down-regulatory effect of SP was reversed by spantide, a SP antagonist. Lesional psoriatic keratinocytes showed a similar, but weaker, response when compared with normal keratinocytes. These data suggested that SP might modulate IL-6 synthesis of keratinocytes in either physiologic or pathologic conditions such as psoriasis.
J Dermatol Sci 1999 Dec
PMID:The effects of substance P and vasoactive intestinal peptide on interleukin-6 synthesis in cultured human keratinocytes. 1065 Dec 25


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