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Biomedical subjects

K Bendtzen

Publications and source records attributed to K Bendtzen.

At least 253 records · Page 14Linked to original sources
PubMed1989

Auto-antibodies to tumour necrosis factor alpha in healthy humans and patients with inflammatory diseases and gram-negative bacterial infections.

A semi-quantitative immunoblotting method was developed to screen for serum auto-antibodies against tumour necrosis factor alpha (TNF alpha). Forty nitrocellulose strips containing identical amounts of human recombinant TNF alpha (rTNF alpha) were prepared for each set-up, and the anti-TNF alpha antibody immunoreactivities were scored according to the density of the resulting colour reaction. A significant number of sera from apparently healthy donors contained detectable auto-antibodies to TNF alpha (40%), while the strongest reaction was observed in 8%. A higher prevalence of anti-TNF alpha antibodies was found in sera from patients with Gram-negative bacterial septicaemia (66%), cystic fibrosis with chronic Pseudomonas aeruginosa lung infection (72%), and various rheumatic diseases (61%). The antibodies in sera from these patients belonged primarily to the IgG and IgM classes, the latter exhibiting the strongest response. Longitudinally collected serum samples from patients in septic endotoxin shock revealed that the anti-TNF alpha antibodies were induced initially during septicaemia, reaching maximum reactivities within the first week and returning to low or undetectable levels on days 9-20.

Adolescent↗
PubMed1989

Epidermal tumour necrosis factor alpha and interleukin 6-like activities in AIDS-related Kaposi's sarcoma. An immunohistological study.

Biopsies from 6 patients with AIDS and Kaposi's sarcoma (KS) in the tumour stage, and 6 healthy controls, were immunohistologically examined for the presence of tissue-bound tumour necrosis factor alpha (TNF alpha) and interleukin 6 (IL-6) in the skin. TNF alpha was demonstrated using specific polyclonal antiserum to human recombinant TNF alpha. IL-6 was visualized indirectly using a polyclonal antiserum to partially purified human crude supernatants of activated human blood monocytes, followed by absorption with recombinant human IL-6. The cytokines were found identically located in epidermal cell membranes in stratum granulosum and spinosum of the epidermis from unaffected skin in both AIDS patients and in controls. Biopsies from KS elements showed markedly increased epidermal staining for both TNF delta and IL-6. It was not possible to detect TNF alpha or IL6 in the endothelial cells of the tumour. The observation of increased amounts of epidermal-bound TNF alpha and IL-6 in AIDS-related KS elements supplements previous studies indicating that the skin plays an active immunoinflammatory role in patients with AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1989

IL-6 gene polymorphism in rheumatoid arthritis, pauciarticular juvenile rheumatoid arthritis, systemic lupus erythematosus, and in healthy Danes.

The restriction enzymes MspI and BglII identify two different two-allele restriction fragment length polymorphisms (RFLP) in the human IL-6 genes of healthy Danes. Co-dominant segregation was demonstrated for both marker-systems and the test for Hardy-Weinberg equilibrium showed no significant deviation from expectations. There is a strong correlation between the two marker systems. The two IL-6 RFLP's were studied in Danish patients with rheumatoid arthritis, pauciarticular juvenile rheumatoid arthritis, and systemic lupus erythematosus. The frequencies of the MspI and BglII marker phenotypes did not differ between healthy controls and the three disease groups. No extra or missing DNA fragments were observed in the disease groups when compared with controls.

Arthritis, Juvenile↗
PubMed1989

Studies on the mechanisms causing inhibition of insulin secretion in rat pancreatic islets exposed to human interleukin-1 beta indicate a perturbation in the mitochondrial function.

This study aimed at a more detailed characterization of the mechanisms by which interleukin 1 (IL-1) inhibits insulin secretion. For this purpose, isolated rat pancreatic islets were kept in tissue culture for 5 days in medium RPMI 1640 plus 10% calf serum. The islets were subsequently transferred to the same culture medium containing various test substances plus 1% human serum with or without 25 U/ml human recombinant IL-1 beta. After a culture period of 48 h the islet structure was examined in the electron microscope and the islet function studied in short term incubations in the absence of IL-1. Islets exposed to IL-1 showed ultrastructural signs of degeneration in 10-20% of the B cells while such changes were not found in other types of islet cells. An increased number of secondary lysosomes and occasional myelin figures were observed in the B cells exposed to IL-1. These ultrastructural alterations were, however, reversed in islets cultured in cytokine-free medium for 6 days after the IL-1 treatment. In islets cultured in the presence of 11.1 mM glucose only, or 11.1 mM glucose plus 10 mM nicotinamide, 61 mM dimethyl area, 2 micrograms/ml indomethacin, 10 microM 4-bromophenacyl bromide or 10 microM nordihydroguaiaretic acid, 10 microM phenantroline, and 0.1 or 1.0 microgram/ml cyclosporin A, IL-1 reduced the insulin release by 64-85%. Culture at 5.6 mM glucose did not modify the IL-1-induced inhibition of insulin release, whereas a significant protective effect was observed at 28 or 56 mM glucose. The DNA content in IL-1-exposed islets cultured at 11.1 mM glucose was decreased by about 20% but not in islets cultured at other glucose concentrations. The D-[5-3H]glucose utilization at 16.7 mM glucose was unaffected by IL-1, whereas the oxidation of D-[6-14C]glucose was reduced by 50%. The present results suggest that IL-1-induced inhibition of insulin secretion is related to a disturbed mitochondrial function. This effect is not counteracted by a poly(ADP-ribose) synthetase inhibitor, a hydroxyl radical scavenger, an iron chelator, a T lymphocyte-specific immunosuppressive drug, or inhibitors of phospholipase A2 or inhibitors of prostaglandin and leukotriene synthesis. Thus, IL-1-induced inhibition of insulin secretion seems not to be mediated by the same mechanisms as those causing alloxan- or streptozotocin-induced damage of B cells. Furthermore, the action of IL-1 does not appear to be mediated via arachidonic acid metabolism. Glucose affords some protection, probably by enhancing the B cell mitochondrial function.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetophenones↗
PubMed1989

Differential sensitivity to beta-cell secretagogues in cultured rat pancreatic islets exposed to human interleukin-1 beta.

The early stages of insulin-dependent diabetes mellitus are characterized by a selective inability to secrete insulin in response to glucose, coupled to a better response to nonnutrient secretagogues. The deficient glucose response may be a result of the autoimmune process directed toward the beta-cells. Interleukin-1 (IL-1) has been suggested to be one possible mediator of immunological damage of the beta-cells. In the present study we characterized the sensitivity of beta-cells to different secretagogues after human recombinant IL-1 beta (rIL-1 beta) exposure. Furthermore, experiments were performed to clarify the biochemical mechanisms behind the defective insulin response observed in these islets. Rat pancreatic islets were isolated and kept in tissue culture (medium RPMI-1640 plus 10% calf serum) for 5 days. The islets were subsequently exposed to 60 pM human recombinant IL-1 beta during 48 h in the same culture conditions as above and examined immediately after IL-1 exposure. The rIL-1 beta-treated islets showed a marked reduction of glucose-stimulated insulin release. Stimulation with arginine plus different glucose concentrations, and leucine plus glutamine partially counteracted the rIL-1 beta-induced reduction of insulin release. The activities of the glycolytic enzymes hexokinase, glucokinase, and glyceraldehyde 3-phosphate dehydrogenase, were similar in control and IL-1-exposed islets. Treatment with IL-1 also did not impair the activities of NADH+- and NADPH+-dependent glutamate dehydrogenase, glutamate-aspartate transaminase, glutamate-alanine transaminase, citrate synthase, and NAD+-linked isocitrate dehydrogenase. The oxidation of D-[6-14C]glucose and L-[U-14C]leucine were decreased by 50% in IL-1-treated islets. Furthermore, there was a significant decrease in the ratios of [2-14C]pyruvate oxidation/[1-14C]pyruvate decarboxylation and L-[U-14C]leucine oxidation/L-[1-14C]leucine decarboxylation, indicating that IL-1 decreases the proportion of generated acetyl-coenzyme-A residues undergoing oxidation. However, in the presence of IL-1 there was a significant increase in L-[U-14C]glutamate oxidation. These combined observations suggest that exposure to IL-1 induces a preferential decrease in glucose-mediated insulin release and mitochondrial glucose metabolism. This mitochondrial dysfunction seems to reflect an impairment in proximal steps of the Krebs cycle. It is conceivable that the IL-1-induced suppression and shift in islet metabolism can be an explanation for the beta-cell insensitivity to glucose observed in the early phases of human and experimental insulin-dependent diabetes mellitus.

Animals↗
PubMed1989

Interleukin-6 in the epidermis of patients with psoriasis before and during PUVA treatment.

Biopsies from lesional and unaffected skin of 6 patients with psoriasis, taken before and during treatment with psoralen plus UVA (PUVA) were examined immunohistologically, using partially purified polyclonal antibodies to crude supernatants of activated human blood monocytes. By absorption with recombinant derived human monokines, we were able to demonstrate that interleukin-6 (IL-6) (but not IL-1 alpha or IL-1 beta) was located in a laminar and granular pattern in stratum corneum, and on epidermal cell membranes in the viable cellular epidermis. Before PUVA treatment, the intensity and the extension of staining for IL-6 were both markedly increased in lesional skin compared with uninvolved skin. A weaker staining for IL-6 was observed in lesional skin, simultaneous with the clinical improvement of psoriasis. The staining patterns for IL-6 in biopsies from cleared lesional skin and uninvolved psoriatic skin were identical at the conclusion of therapy.

Adult↗
PubMed1989

Expression of interleukin-6-like molecules and tumour necrosis factor after topical treatment of psoriasis with a new vitamin D analogue (MC 903).

Skin biopsies from 5 patients with chronic plaque psoriasis were examined to test the effect of topical treatment with a new synthetic vitamin D3 analogue, MC 903, on epidermal interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF alpha). Skin biopsies, taken before therapy and after one and 2 weeks of therapy were examined immunohistologically. IL-6 was visualized using a partially purified polyclonal antiserum to crude supernatants of activated human blood monocytes before and after absorption with recombinant human IL-6. TNF alpha was demonstrated using a specific polyclonal antiserum to human recombinant TNF alpha. Both the intensity and extension of staining for IL-6, but not for TNF alpha, were increased in lesions compared with unaffected skin. During therapy with MC 903 a decline in the staining intensity for IL-6, but not for TNF alpha, was observed in both lesional and unaffected skin. Placebo-treated lesions, however, remained unchanged.

Adult↗
PubMed1989

Possible role of IL-1, TNF-alpha, and IL-6 in insulin-dependent diabetes mellitus and autoimmune thyroid disease. Thyroid Cell Group.

Recent experiments indicate a central role of macrophages (M phi), and natural killer (NK) cells, and their products IL-1, IL-6 and TNF alpha in autoimmune endocrine diseases. Intermediate levels of IL-1 alpha/beta inhibit the function of pancreatic beta-cells and thyrocytes, an effect potentiated by TNF alpha. In contrast, low levels of IL-1 potentiate the secretion of insulin and thyroid hormones, and intermediate levels of IL-6 double glucose-induced insulin production by beta-cells. Intermediate and high levels of IL-1 and IL-6 are cytotoxic to normal beta-cells. IL-1 induces IL-6 in isolated islets and in thyrocytes. The cytokines may play a role in the physiological regulation of endocrine functions, for instance during conditions of stress. The genes for TNF alpha and -beta, both located in the MHC region, and IL-6 are polymorphic, and specific alleles may control the amount of cytokine produced. Specific TNF alpha/beta alleles may be in linkage disequilibrium with HLA alleles known to be positively or negatively associated with endocrine and other autoimmune diseases.

Animals↗
PubMed1988

1 alpha,25-Dihydroxyvitamin D3 and a novel vitamin D analogue MC 903 are potent inhibitors of human interleukin 1 in vitro.

1 alpha,25-dihydroxycholecalciferol (1,25(OH)2D3) inhibits the lymphocyte growth hormone, interleukin 2. Since its production is dependent upon interleukin 1 (IL-1) produced by antigen-presenting cells, we tested five vitamin D3 analogues for effects on the production and function of human natural and recombinant IL-1. The production was not affected, but 1,25(OH)2D3 (greater than 10(-11) M) and a synthetic derivative MC 903 (greater than = 10(-10) M) inhibited the proliferation of mouse thymocytes to IL-1. The vitamins failed to affect the cytotoxic activity of tumor necrosis factor. 1,25(OH)2D3 may play a physiological immunomodulatory role as a selective inhibitor of the function of IL-1, and MC 903 may prove clinically useful in this regard because of its limited calcium metabolic activity.

Animals↗
PubMed1988

Modulation of human neutrophil and monocyte chemotaxis and superoxide responses by recombinant TNF-alpha and GM-CSF.

The effects of recombinant TNF and GM-CSF on human peripheral blood neutrophil and monocyte chemotaxis and the superoxide response were studied. TNF exhibited a slight chemotactic activity for both cell types. Preincubation of neutrophils with as little as 40 units/ml strongly inhibited the neutrophil chemotaxis towards f-Met-Leu-Phe. The inhibition of monocyte chemotaxis required higher concentrations of TNF (greater than 400 units/ml). TNF at concentrations higher than 500 units/ml enhanced the generation of superoxide anions by neutrophils stimulated with f-Met-Leu-Phe. In contrast, TNF even at 2,000 units/ml did not prime monocytes for enhanced superoxide response. GM-CSF alone did not exhibit any chemotactic activity for any of the cell types tested. Preincubation of cells with GM-CSF inhibited chemotaxis of neutrophils but not of monocytes. GM-CSF was as potent as TNF in enhancing the generation of superoxide response by neutrophils. However, GM-CSF did not have any effect on monocyte superoxide response. The priming ability of TNF and GM-CSF on neutrophils was heat-sensitive. We conclude that TNF and GM-CSF play a more pronounced regulatory role on neutrophils than on monocytes. Inhibition of neutrophil chemotaxis followed by enhancement of the superoxide response by TNF and GM-CSF may provide an attractive mechanism by which these cytokines assist in fighting invading microorganisms.

Chemotaxis, Leukocyte↗
PubMed1988

Recombinant interleukin 1 alpha and beta prime human monocyte superoxide production but have no effect on chemotaxis and oxidative burst response of neutrophils.

We report that recombinant human IL 1 alpha and beta and the two synthetic short fragments 163-171 and 226-254 do not exhibit chemotactic activity for human peripheral blood neutrophils and monocytes. These products up to concentrations of 4 X 10(4) units/ml failed to show chemotactic activity. Furthermore, IL 1 alpha and beta failed to generate chemotactic factors from human serum. Recombinant IL 1 alpha, IL 1 beta, or IL 1 beta fragments 163-171 and 226-254 did not induce any superoxide response by monocytes or neutrophils. However, exposure of monocytes to recombinant IL 1 alpha or IL 1 beta resulted in enhanced generation of superoxide response following stimulation with PMA. No priming was observed in neutrophils. These results suggest that IL 1 alpha and beta are involved in regulation of monocyte oxidative burst response, but play no direct regulatory role on neutrophil function.

Chemotaxis, Leukocyte↗
PubMed1988

Immunohistological detection of interleukin I-like molecules and tumour necrosis factor in human epidermis before and after UVB-irradiation in vivo.

Skin biopsies from five healthy subjects, taken before and after UVB irradiation, were examined using immunohistological techniques for the cytokines interleukin-I (IL-I) and tumour necrosis factor (TNF). Using polyclonal specific antibodies against IL-I and TNF, the two cytokines appeared identically located on the epidermal cell membranes of the stratum granulosum and stratum spinosum in unexposed skin. After UVB-exposure, the staining intensity for both IL-I/epidermal cell derived thymocyte-activating factor (ETAF) and TNF was markedly increased, and the epidermal staining included the basal cell layer. Immunohistological investigation of tissue-bound epidermal cytokines may be valuable in the study of skin diseases.

Adult↗
PubMed1988

Association between HLA-DR2 and production of tumour necrosis factor alpha and interleukin 1 by mononuclear cells activated by lipopolysaccharide.

The production of tumour necrosis factor (TNF) and interleukin 1 (IL-1) by lipopolysaccharide-activated mononuclear cells from 39 healthy donors was studied in vitro by bioassay and ELISA. The donors were typed for HLA-A, -B, -C, -DR, and -DP antigens. There was no detectable production of TNF beta (lymphotoxin). The intracellular levels of bioactive TNF alpha were minimal or undetectable in all cases. Cells from HLA-DR2+ individuals secreted significantly lower amounts of TNF alpha than cells from HLA-DR2- donors [2 ng/ml (1.5-4.4) and 7.5 ng/ml (3.9-8.3) respectively (medians 25-75%); P less than 0.01]. The difference disappeared if the cells were preactivated for 2 days with 1000 U/ml of recombinant gamma interferon (rIFN-gamma). In some individuals, the TNF alpha response increased considerably after IFN-gamma priming, in particular in those possessing the HLA-DR2 antigen. In contrast, there was no detectable difference in the production of IL-1 beta between the donors, and the IL-1 beta response decreased significantly after rIFN-gamma priming in HLA-DR2+ individuals [2.3 ng/ml (1.1-8.4) versus 7.2 ng/ml (5-7.9); P less than 0.05] and in HLA-DR2- individuals [3 ng/ml (1.1-5.3) versus 5.7 ng/ml (3.9-7.5); P less than 0.01]. There was no correlation between the TNF alpha and IL-1 responses and any of the other HLA-DR, -DP, or -B antigens. There was a significant positive correlation between the levels of TNF alpha measured by ELISA and by cytotoxicity assay. However, the TNF alpha-containing supernatants from 9 out of 37 individuals appeared to contain inhibitor(s) of the biological activity of TNF alpha. The presence of inhibitor(s) was not associated with any HLA antigens.

Adult↗