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Biomedical subjects

E Corsini

Publications and source records attributed to E Corsini.

At least 55 records · Page 3Linked to original sources
PubMed1998

Selected new developments in asbestos immunotoxicity.

Research over the past three decades has shown that the mammalian immune system can be altered by the occupational exposure of asbestos. Early clinical studies generally focused on systemic observations of immune alteration such as the number and function of peripheral lymphocytes and monocytes. More recently as the regulatory influence of local immunity in health and disease becomes more defined, immunologic changes occurring in the lung, the primary target organ of asbestos, have been significant areas of investigation. This review will focus on recent studies that examine the influence of asbestos on pulmonary immunity as well as the role of host immune competence in asbestos-related disease.

Animals↗
PubMed1997

Role of mitochondria and calcium ions in tributyltin-induced gene regulatory pathways.

Tributyltin (TBT) salts are potent skin irritants both in humans and rodents. Data in the literature indicate mitochondria as target of TBT effects. Here, we investigate the early intracellular molecular events that follow TBT treatment and the relevance of calcium ions and mitochondria in gene-regulatory signaling pathways. Confluent HEL30 cells were treated with increasing doses of TBT (0-5 microM). At different times thereafter, the level of intracellular Ca2+, the cellular oxidative activity, nuclear factor-kappaB (NF-kappaB) activation, and IL-1alpha production were measured. TBT induced a dose-related increase of intracellular Ca2+ that reached the plateau 4 min following treatment. The increase of intracellular Ca2+ was followed by an increase in cellular oxidative activity as measured by DCFH oxidation (15 min) that preceded NF-kappaB activation (30 min) and IL-1alpha production (4 hr). All these events can be almost completely abrogated by BAPTA, an intracellular Ca2+ chelator. Furthermore, the modulation of cellular oxidative activity induced by TBT observed with rotenone, an inhibitor of the electron entry from complex I to ubiquinone, or after prolonged treatment with ethidium bromide, an inhibitor of mitochondrial DNA and RNA synthesis, indicates mitochondria as an important intracellular source of reactive oxygen species. These findings indicate the rise in intracellular Ca2+ as the starting event and indicate the role of mitochondria as the source of second messenger molecules essential for TBT-induced NF-kappaB activation and IL-1alpha production.

Analysis of Variance↗
PubMed1997

IL-10 production in multiple sclerosis patients, SLE patients and healthy controls: preliminary findings.

IL-10 is a cytokine with suppressive effects on (auto) antigen presentation and T-cell-mediated immune reactions, but is also capable of stimulating polyclonal IgG synthesis. Recent evidence suggests its involvement in multiple sclerosis (MS) and systemic lupus erythematosus (SLE). We assessed PBMNC IL-10 release in MS and SLE patients before and after in vivo prednisone or methylprednisolone treatment. The SLE patients showed a high level of IL-10 release by unstimulated PBMNCs, whereas the PHA-stimulated PBMNCs from MS patients produced large amounts of the cytokine.

Adult↗
PubMed1997

Thyroid peroxidase as toxicity target for dithiocarbamates.

In vivo ethylenebisdithiocarbamates and ETU are toxic to the thyroid gland. Since the molecular target of these compounds is thought to be thyroid peroxidase (TPO) which catalyzes the transfer of iodine to thyroglobulin, we examined the effect of these compounds on peroxidative activity in Chinese hamster ovary (CHO) cells transfected with the human TPO gene. The activity was inhibited by 50 microM ETU, 5 microM ziram and 5 microM zineb, the last-mentioned effect being irreversible in the absence of iodide. Thiram had no effect. By contrast, the iodinating activity of TPO was blocked only by 5 microM ETU and 50 microM zineb but not by the other compounds. The effect on TPO-catalysed iodination could explain the differences in thyrotoxicity of these compounds in vivo.

Animals↗
PubMed1997

Immunological monitoring of azathioprine treatment in multiple sclerosis patients.

Despite the longstanding clinical use of azathioprine as an immunosuppressive agent in multiple sclerosis, little is known about the action of this drug on a number of parameters of putative pathogenic relevance in the disease. Eleven patients with multiple sclerosis, treated with azathioprine 2.5-3 mg/kg per day, and six untreated patients were studied with serial blood sampling for 1 year. The following immunological parameters were investigated: peripheral blood lymphocyte subsets, natural killer activity, serum IgG, IgM, ICAM-1 and tumour necrosis factor alpha (TNF-alpha). The most relevant changes included a decrease in CD3- CD56+ cells, an increase in CD4+ CD45RA+ cells and a decrease in TNF-alpha levels only in treated patients, while no changes occurred in untreated patients over a 1-year period. The decrease in TNF-alpha levels and the increase in "suppressor-inducer" lymphocytes could reduce chronic inflammation in multiple sclerosis, and paralleled an overall favourable clinical response to azathioprine treatment in our patients.

Azathioprine↗
PubMed1997

Effects of beta-IFN-1b treatment in MS patients on adhesion between PBMNCs, HUVECs and MS-HBECs: an in vivo and in vitro study.

The in vivo effects on the expression of adhesion molecules and on the adhesion between mononuclear cells and multiple sclerosis human brain endothelial cells (MS-HBECs) were investigated at the beginning of beta-IFN-1b treatment of MS patients. MS-HBECs were isolated from a surgical specimen obtained from an MS patient undergoing brain surgery for vascular aneurysm. 48 h after the first single administration of beta-IFN-1b, PBMNCs of 10 MS patients were analyzed for HLA-DR, CD11a, CD18 and VLA-4 expression and the adhesion between PBMNCs and both stimulated and unstimulated MS-HBECs evaluated. sICAM-1 and sVCAM-1 dosage in the serum of the patients was checked as well. The experiments were repeated using HUVECs in order to detect possible endothelial organ-specific differences. The experiments were also performed after six months of beta-INF-1b treatment on HUVECs. No significant effects on mononuclear cells/endothelium adhesion were detected at 48 h, but adhesion of PBMNCs to HUVECs decreased at six months. An increase in HLA-DR and VLA-4 and a decrease of CD18 was detected in monocytes. The serum level of sVCAM-1 increased at T2 and was still higher than at T0 at six months. The effect of the beta-IFN-1b treatment on both MS-HBECs and HUVECs, was selectively studied in vitro by testing the expression of cytokine-induced adhesion molecules HLA-DR, ICAM-1 and VCAM-1. The in vitro experiments confirmed that beta-IFN-1b is able to antagonize gamma-IFN-induced HLA-DR expression on MS human brain endothelial cells without relevant effects on VCAM-1 and ICAM-1.

Adult↗
PubMed1997

Induction of tumor necrosis factor-alpha in vivo by a skin irritant, tributyltin, through activation of transcription factors: its pharmacological modulation by anti-inflammatory drugs.

Skin irritant reactions are under the control of a network of cytokines and lipid mediators. This study characterized the production of tumor necrosis factor-alpha (TNF) induced by a skin irritant treatment, tributyltin (TBT), in mice through transcription factor activation and its pharmacologic modulation by anti-inflammatory agents. The ears of BALB/c mice were painted with different amounts of TBT (67-536 nmol in acetone) or with acetone alone. At different times thereafter, TNF production was analyzed both at the mRNA and protein level, by semiquantitative RT-PCR and L929 cytotoxicity assay, respectively. TBT induced rapid (1 h) TNF gene expression and protein synthesis. Maximal TNF production was observed 2 h after treatment. The production of TNF was paralleled by accumulation of skin water; this was partially prevented by intraperitoneal injection of antibody against murine TNF. These data indicate that skin irritation induced by TBT is attributable, in addition to the actions of other inflammatory mediators, to the action of keratinocyte-derived TNF. TNF production was preceded by a rapid (5 min) activation of nuclear factor-kappaB (NF-kappaB), which was also maximal 30 min after treatment. TBT-induced accumulation of skin water and TNF production were significantly reduced by topical treatment with dexamethasone and pentamidine, two anti-inflammatory agents. Interestingly, dexamethasone, but not pentamidine, decreased TBT-induced NF-kappaB activation, confirming in vivo that the glucocorticoid receptor interacts functionally within the nucleus with other transcription factors opposing one another's activity.

Animals↗
PubMed1997

Reduced adhesion of PBMNCs to endothelium in methylprednisolone-treated MS patients: preliminary results.

Methylprednisolone (MP) is a synthetic steroid commonly used in the treatment of multiple sclerosis (MS) relapses. It has a wide spectrum of activities on immune cells: it might also act by preventing mononuclear cell/endothelium adhesion. We studied adhesion phenomena between cultured human umbilical vein endothelial cells (HUVECs) and PBMNCs (CD45+, CD14+) from 6 MS patients treated in vivo with MP. We also studied fluctuations in CD11a and CD18 levels on lymphocytes and monocytes, as well as changes in serum sICAM-1 and sVCAM-1 concentrations. After MP treatment, PBMNCs adhesion to endothelium decreased at 3 h, while it went back to baseline levels at 24 h. A tendency to increase in both CD11a and CD18 on the surface of lymphocytes was detected, while an increase in serum sVCAM-1 was seen at 3 h.

Adult↗
PubMed1997

Epidermal stratification reduces the effects of UVB (but not UVA) on keratinocyte cytokine production and cytotoxicity.

Ultraviolet (UV) radiation induces cytokine release from cultured keratinocytes as well as from epidermis in vivo. The purpose of this study was to determine whether differentiation of cultured keratinocytes into stratified epithelium decreases the effects of UVA and UVB radiation on cytokine release. Interleukin-1 (IL-1) alpha, IL-1 beta and tumor necrosis factor (TNF)-alpha release from human keratinocytes and reconstituted human epidermis was measured after exposure to UVA or UVB radiation. Release of IL-1 alpha, IL-1 beta, and TNF-alpha was induced by both UVA and UVB radiation from both keratinocytes and reconstituted epidermis. Release of these cytokines was correlated with cytotoxicity. Keratinocyte cultures were far more sensitive to UVB radiation than reconstituted epidermis, in terms of both cytotoxicity and cytokine release. In contrast, epidermal stratification/differentiation had much less effect on the sensitivity to UVA radiation. We conclude that epidermal stratification and the formation of a stratum corneum provide protection against UVB radiation but have limited barrier effect against UVA radiation.

Anti-Inflammatory Agents↗
PubMed1997

Differential induction of cutaneous TNF-alpha and IL-6 by topically applied chemicals.

BACKGROUND: Increasing evidence shows that contact allergens and skin irritants can induce or upregulate the cutaneous expression of cytokines, including those that are required for the initiation of immune responses and which participate in inflammatory reactions. OBJECTIVE: The present investigation compared the ability of the skin allergens oxazolone and 2,4-dinitrochlorobenzene (DNCB) and the skin irritant benzalkonium chloride (BZC) to stimulate the cutaneous expression of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in mice. RESULTS: Each chemical tested induced the dose-dependent production of IL-6 with similar kinetic profiles. BZC was less effective at provoking increases in this cytokine; concentrations (1%) that caused marked edema failed to stimulate significant changes in IL-6 expression. Under conditions of topical exposure in which each of these chemicals caused a vigorous inflammatory response in the skin, as measured by induced edema and the increased production of IL-6, only oxazolone and DNCB stimulated expression of TNF-alpha. The failure of BZC to initiate TNF-alpha production in the skin was not attributable to inhibition of the bioassay used to measure this cytokine and was apparently independent of the stimulation by this chemical of TNF-alpha inhibitory factors. CONCLUSION: These data indicate that not all chemicals that have the ability to cause skin irritation and cutaneous inflammation will elicit detectable TNF-alpha responses and that characterization of cutaneous irritants and allergens on the basis of induced cytokine expression patterns in the skin must be approached with caution.

Adjuvants, Immunologic↗
PubMed1996

NF-kappaB activation by triphenyltin triggers apoptosis in HL-60 cells.

Trisubstituted organotin pesticides are lethal for different cell types. In this study we investigated whether triphenyltin chloride (TPT) causes apoptosis in HL-60 promyelocytic cells and, if so, by what mechanisms. We report that 5 microM TPT increased intracellular Ca2+ in HL-60 cells within seconds; concomitantly actin depolymerization was detected 30 s and 1 min after the treatment. This was followed 15 min later by NF-kappaB activation, and apoptotic bodies and DNA fragmentation were evident after 3 and 6 h, respectively. At these times TPT also induced the release of tumor necrosis factor-alpha (TNF-alpha). Prior treatment of the cells with a polyclonal antibody to human TNF-alpha abolished TPT-induced DNA fragmentation, which suggests that the ultimate effect of TPT may be mediated by TNF-alpha. Prior treatment of the cells with 100 microM pyrrolidine dithiocarbamate, an antioxidant and potent inhibitor of NF-kappaB activation, prevented actin depolymerization, NF-kappaB activation, and DNA fragmentation, although it did not affect TPT-induced Ca2+ mobilization. These findings suggest that TPT increases intracellular Ca2+, alters actin polymerization and the cytoskeleton, and induces NF-kappaB activation, TNF-alpha synthesis, DNA degradation, and apoptosis. Reactive oxygen species seem to be essential to NF-kappaB activation, TNF-alpha synthesis, and the subsequent steps.

Actins↗
PubMed1996

Endogenous interleukin-1 alpha associated with skin irritation induced by tributyltin.

Tributyltin (TBT) salts are well-known skin irritants in both human and rodents. This study investigated the role of interleukin-1alpha (IL-1alpha) in the process in mice and in murine keratinocytes. The ears of Balb/c mice were painted with different amounts of TBT (67-536 nmol in acetone) or with acetone alone. Two hours later there was dose-related production of IL-1alpha along with ear swelling and accumulation of skin water, all of which were partially prevented by intraperitoneal injection of antibody against murine IL-1alpha. By reverse transcription-polymerase chain reaction we were able to show that the neutralizing antibody also partially prevented TBT-induced in vivo IL-6 expression but no TBT-induced TNF-alpha expression, suggesting a paracrine effect of IL-1alpha on IL-6 production but not TNF-alpha expression and indicating that other inflammatory mediators are involved. TBT induced both intracellular production of IL-1alpha and its release into culture medium in a murine keratinocyte cell line (HEL30). IL-1alpha production was inhibited by addition of a neutralizing antibody against IL-1alpha, which suggests an autocrine effect of IL-1alpha on its own production. The intracellular production of IL-1alpha could he significantly inhibited by prior treatment with antioxidants, which strongly suggests a role for oxidative species in the mechanism of action of TBT in IL-1alpha induction. The complex-1 inhibitor rotenone also significantly inhibits IL-1alpha production. Since TBT causes disturbances in the respiratory chain in mitochondria, the mechanism of its action may be the production of reactive oxygen intermediates at the ubiquinone site, which activate transcription factors and promote IL-1alpha synthesis.

Animals↗
PubMed1996

Low serum interleukin-10 levels in multiple sclerosis: further evidence for decreased systemic immunosuppression?

Serum interleukin 10 (IL10) levels were assessed in patients with multiple sclerosis who were either in a stable or active clinical condition. The levels were compared with values in healthy controls. Lower IL10 levels than in controls were seen in multiple sclerosis patients, regardless of clinical disease activity. Low IL10 levels were also seen in patients with systemic lupus erythematosus. No clear-cut relationships emerged between IL10 levels and those of tumour necrosis factor alpha and transforming growth factor beta, or between IL10 and lymphocyte subsets in peripheral blood.

Adult↗
PubMed1996

Human brain endothelial cells and astrocytes produce IL-1 beta but not IL-10.

The ability of human brain endothelial cells to produce mRNA for interleukin-10, and release IL-10 in culture supernatants after in vitro stimulation with LPS, TNF-alpha and gamma-IFN was assessed and compared to that of astrocytes, peripheral blood mononuclear cells and human umbilical vein endothelial cells. IL-1 beta and beta 2-microglobulin release were also analysed. IL-10 and TNF-alpha mRNA presence was investigated in normal brain as well as in three plaques from two multiple sclerosis patients. While increased IL-1 beta and beta 2-microglobulin release in the supernatants of stimulated cells could be detected in all the studied cell lineages, IL-10 mRNA and protein release was only seen in LPS-stimulated PBMNCs. Similarly, mRNA for IL-10 was not detected in CNS tissues, while TNF-alpha was present in all plaques. The lack of production of significant amounts of IL-10 by astrocytes and human brain endothelial cells suggests that these cells may not be the primary source of in vivo IL-10-mediated down-regulation of immune reactions within the central nervous system.

Adult↗
PubMed1996

Role of mitochondria in tributyltin-induced interleukin-1alpha production in murine keratinocytes.

Tributyltin (TBT) salts are well known skin irritants in rodents and humans. TBT induced both the intracellular production of interleukin-1alpha (IL-1alpha) and its release into culture medium in a murine keratinocyte cell line (HEL30). Here, we report that mitochondria are important for TBT-induced IL-1alpha production. Confluent cells were treated with increasing concentrations of TBT (0--2.5 microM) or dimethylsulfoxide as vehicle control. At different times thereafter (0--24 h), nuclear extracts were analyzed for nuclear factor-(kappa)B (NF-(kappa)B) binding activity by electrophoretic mobility shift assay, and the released and cell-associated IL-1alpha was measured by enzyme-linked immunosorbent assay. TBT induced a direct and concentration-related activation of NF-(kappa)B, which peaked at 2 h and was blocked by pyrrolidinedithiocarbamate, a potent NF-(kappa)B inhibitor, and rotenone, an inhibitor of the electron entry from complex I to ubiquinone. Rotenone also induced a concentration-related inhibition of IL-1alpha synthesis induced by TBT, but rotenone did not completely abrogate TBT-induced IL-1alpha production, which suggests that other transcription factors may be involved in IL-1alpha production. Prolonged treatment with ethidium bromide, an inhibitor of mitochondrial DNA and RNA synthesis, was used to partially deplete cells of functional mitochondria. After 5 d of treatment, mitochondrial conversion of tetrazolium bromide to formazan was reduced by 50%, and IL-1alpha release was decreased by 65%, whereas no induction of intracellular IL-1alpha was observed. This effect was not due to inhibition of protein synthesis, because identical incorporation of [3H]leucine into protein in control and ethidium bromide-treated cells was identical. This impairment of mitochondrial metabolism inhibited NF-(kappa)B activation by TBT. These findings indicate that mitochondria may be the source of second messenger molecules important for TBT-induced IL-1alpha production.

Animals↗
PubMed1995

Cloning of a new FRTL5-derived cell line stably expressing active human thyroid peroxidase.

A full-length cDNA clone for human thyroid peroxidase inserted into the mammalian cell expression vector pECE was stably transfected into the rat thyroid cell line FRTL5. Clones expressed immunologically and enzymatically assessed human thyroid peroxidase protein. Methimazole (25 microM) inhibited the thyroid peroxidase activity dose-dependently and this effect was completely antagonised by 100 microM NaI. Ethylenethiourea, metabolite of dithiocarbamate pesticides, inhibited the enzyme at 50 microM. Thus, we have obtained thyroidal cells stably expressing enzymatically active human thyroid peroxidase which can be pharmacologically modulated and studied.

Animals↗
PubMed1995

In vitro mechanism(s) of ultraviolet-induced tumor necrosis factor-alpha release in a human keratinocyte cell line.

It has been demonstrated that ultraviolet (UV) irradiation is able to induce both in vivo and in vitro, tumor necrosis factor-alpha (TNF) release. The purpose of the present study was to evaluate, using a human keratinocyte cell line NCTC 2544, the mechanism(s) of UV-induced TNF release and the ability of commonly used sunscreens to modulate UV-induced TNF release. TNF release can be partially prevented both by adding an anti-human IL-1 alpha antibody after irradiation, suggesting an autocrine effect of IL-1 alpha in inducing TNF release, and by adding antioxidants indicating also a role of oxidant species. TPCK, a I kappa-B alpha protease inhibitor, was able to virtually abolish UV-induced TNF release, indicating that UV-induced TNF release requires NF-kappa B activation. Anti-human IL-1 beta antibody was ineffective as expected, considering that keratinocytes are unable to process pre-IL-1 beta to its active form. To evaluate the sunscreen's modulation on UV-induced TNF release, confluent cells were irradiated, in the presence or absence of the tested sunscreens (Uvinul MS40, Uvinul P25 and Uvinul DS49). Different IC50 values could be calculated, which may be related to different UV absorption spectrums: Uvinul MS40 offers great protection by virtue of its broader absorption spectrum, closely followed by Uvinul P25 and finally by Uvinul DS49.

4-Aminobenzoic Acid↗