Cyclosporine for juvenile dermatomyositis.
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Adolescent↗
Biomedical subjects
J M Dayer
Publications and source records attributed to J M Dayer.
Diminished IL-2-induced gamma-interferon production by unstimulated peripheral-blood lymphocytes in rheumatoid arthritis.
A diminished gamma-interferon (IFN-gamma) production by T cells from patients with rheumatoid arthritis (RA) in response to autologous stimulation coincides with a defective regulation of Epstein-Barr virus (EBV) transformation and is in part due to monocyte-produced interleukin-1 (IL-1) inhibitor and prostaglandins. Since IL-2 can act directly on unstimulated T-cells to induce IFN-gamma production we have now examined the effect of recombinant IL-2 (rIL-2) on purified resting T lymphocytes from RA patients. Treatment with rIL-2(25 U/ml) of lymphocytes from 15 controls led to an increased production of 72-h supernatant EBV-inhibitory activity (19 +/- 4% SE without; 48 +/- 7% with rIL-2), but had only minimal or no effect on gamma-interferon production by E-rosetting lymphocytes from 15 patients with active RA. This defect could not be corrected by adding indomethacin to RA cultures.
Adult↗
Human recombinant interleukin-1 beta and -alpha, but not recombinant tumor necrosis factor alpha stimulate ACTH release from rat anterior pituitary cells in vitro in a prostaglandin E2 and cAMP independent manner.
The pituitary-adrenal axis is known to be stimulated during the acute-phase response. As cytokines play a central role in mediating the constellation of host response occurring during the acute-phase response it was of interest to assess the ability of cytokines to stimulate ACTH secretion from normal pituitary cells in culture. We used human recombinant interleukin-1 beta and -alpha (hrIL1 beta, hrIL1 alpha) and human recombinant tumor necrosis factor alpha (hrTNF alpha) to analyze the ability of these cytokines to induce ACTH secretion from normal rat anterior pituitary cells in culture. We also investigated the possible roles of prostaglandin E2 (PGE2) and cAMP in the cellular transduction mechanism. After 3 days of incubation primary cultures of rat anterior pituitary cells were stimulated for 24 h with either hrIL1 beta, hrIL1 alpha or hrTNF alpha alone or with the addition of dexamethasone or indomethacin. The culture media were analyzed for ACTH, PGE2 and cAMP content. At doses ranging from 0.03 to 30 nM, hrIL1 beta stimulated the release of ACTH and PGE2 in a dose-dependent manner. In contrast, at doses ranging from 3 to 60 nM, hrTNF alpha was unable to stimulate ACTH secretion although it stimulated PGE2 synthesis. Time-course experiments demonstrated that hrIL1 beta (3 nM) stimulates ACTH production over a period of 8, 16 and 24 h, but not after a period of 4 h. In these experiments, hrIL1 beta failed to cause any change in the secretions of growth hormone and luteinizing hormone.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenocorticotropic Hormone↗
Human recombinant interleukin-1 beta decreases plasma thyroid hormone and thyroid stimulating hormone levels in rats.
Thyroid function was investigated in rats treated sc with a single injection of human recombinant interleukin-1 beta (hrIL-1). In 5 h 12.5 micrograms hrIL-1 decreased total serum T4 levels by 30 +/- 2% (P less than 0.01) and serum T3 levels by 35 +/- 4% (P less than 0.001). However free T4 and T3 fractions increased markedly within the first 140 min by 162 +/- 20% (P less than 0.001) and by 55 +/- 4% (P less than 0.001) resulting in a 88 +/- 20% increase in the free T4 concentration (P less than 0.001) but no increase in the free T3 concentration. Serum TSH concentration fell in the 5 h after the hrIL-1 injection by 77 +/- 3% (P less than 0.001). A similar decrease was observed with 0.125 micrograms hrIL-1. Five hours of starvation did not change serum TSH levels, suggesting that the effect of hrIL-1 on TSH was not due to decreased food intake. In order to test whether the decrease in serum TSH was due to an intrapituitary increase in T3, hrIL-1 was injected in hypothyroid rats: the fall of serum TSH was not prevented and it fell in 5 h from 14.05 +/- 0.56 to 9.66 +/- 0.98 ng/ml (31%, P less than 0.01, n = 14). These results suggest that hrIL-1 acts independently of thyroid hormones. Peripheral metabolism of T4 was studied by implanting [125I]T4 secreting minipumps during 14 days. There was no difference in T4 plasma clearance rate between control and treated animals. The fall of serum T4 was therefore explained by decreased secretion and not by increased catabolism since ether link cleavage of T4 and changes in hepatic deiodinase could not be detected. We therefore suggest that hrIL-1 inhibits thyroid function mainly at the hypothalamic-hypophyseal level.
Animals↗
Specific interleukin-1 inhibitor in serum and urine of children with systemic juvenile chronic arthritis.
Interleukin-1 (IL-1) activity and inhibition were studied in serum and urine from nine patients with systemic juvenile chronic arthritis (S-JCA). In afebrile patients IL-1 activity was normal or high. Serum from two afebrile S-JCA patients taken during a period of severe disease activity had an enhancing effect on the activity of exogenous IL-1. Secondary amyloidosis subsequently developed in one of these patients. In contrast, in febrile patients' serum and urine IL-1 activity was low, apparently reflecting the presence of a strong inhibitor of IL-1 activity measured by the inhibition of prostaglandin E2 production by synovial cells. This inhibition was greatest at the time of peak temperature, suggesting the possibility of feedback regulation during fever. This novel identification in S-JCA of a specific IL-1 inhibitor that competes at the IL-1 receptor level may be an important step in the understanding of the pattern of fever and the evaluation of disease in patients with S-JCA.
Adolescent↗
A urine inhibitor of interleukin 1 activity that blocks ligand binding.
Urine from febrile patients was found to contain a novel inhibitor of interleukin 1 (IL-1) bioactivity that blocked the specific binding of radioiodinated IL-1 to its receptor in a dose-dependent fashion. Strong inhibition of IL-1 binding was still obtained when cells were preincubated with the inhibitor and washed, thus suggesting that the inhibitor binds to a surface structure (possibly the IL-1 receptor itself). The inhibitor was distinct from IL-1 as determined by both physical parameters (size and antigenicity) and receptor-binding characteristics (apparent affinity and dissociation rate). These data provide evidence for a physiologic regulator of IL-1 activity that functions in vivo via direct interference with ligand binding.
Animals↗
A urine inhibitor of interleukin 1 activity affects both interleukin 1 alpha and 1 beta but not tumor necrosis factor alpha.
Urine from monocytic leukemia and other febrile patients contains an inhibitor of interleukin 1 (IL-1), as measured by prostaglandin E2 and collagenase production by human fibroblasts and synovial cells. With the use of recombinant IL-1, the IL-1 inhibitor was partially purified by using ammonium sulfate precipitation, anion-exchange, and gel filtration chromatographies. IL-1 inhibitory activity elutes with an 18,000 to 25,000 apparent molecular size. The same fractions also inhibit IL-1 assayed by the proliferation of murine thymocytes and human fibroblasts. Both forms of human recombinant IL-1, IL-1 alpha and IL-1 beta, which show only 26% homology, but nevertheless bind to the same receptor, are affected by this natural inhibitor to the same extent. In contrast, human recombinant tumor necrosis factor, which shares some of the biologic activities of IL-1, is not inhibited by the urinary IL-1 inhibitor. This study shows that the various biologic activities of both forms of human recombinant IL-1 are inhibited by a partially purified natural urine-derived factor.
Cell Division↗
Constitutive and induced expression of the individual HLA-DR beta and alpha chain loci in different cell types.
The HLA-DR subregion of the human major histocompatibility complex encodes molecules involved in the regulation of the immune response. These HLA class II molecules are transmembrane heterodimers composed of an alpha and a beta chain. The polymorphic beta chains are encoded by multiple, highly homologous loci, whereas the alpha chain is encoded by a single, nonpolymorphic locus. HLA-DR is expressed constitutively on B lymphocytes and on activated T lymphocytes. It can also be induced by interferon-gamma on most nonlymphoid cells. In a quantitative study of the expression of the individual DR beta chain loci, we have investigated: the levels of mRNA transcripts of the two functional DR beta loci (beta I and beta III) in B cells of various haplotypes; whether both beta chain loci are expressed in activated T cells and, if so, the level of expression of each; whether both loci are expressed in interferon-gamma-induced nonlymphoid cells. This analysis relied on locus-specific DR beta chain oligonucleotide probes. Expression of both the beta I and the beta III loci was observed in all cell types and in all haplotypes tested. In every case the amount of beta I mRNA was about 5 times higher than that of beta III mRNA. This indicates a controlled and coordinated regulation of the mRNA levels of these two HLA-DR loci under all conditions of major histocompatibility complex class II gene expression.
B-Lymphocytes↗
Purification and characterization of human interleukin-1 alpha produced in Escherichia coli.
The production of human interleukin-1 alpha (IL-1 alpha) in Escherichia coli is described together with a method for its purification. The isolated protein was shown to be pure and physically homogeneous. The in vitro biological activity of IL-1 alpha was tested with the mononuclear-cell factor and the lymphocyte-activating factor assays. The specific activity determined with both assays was about 3 X 10(7) units mg-1 and is similar to that observed with recombinant human IL-1 beta. The purified protein was resolved by chromatofocusing into two species of isoelectric points 5.45 and 5.20 (75% and 25%, respectively, of the total protein). Both species had similar chemical properties and biological activities to the unfractionated protein. The charge difference between the species was attributed to the deamidation of a single Asn or Gln residue.
Amino Acids↗
Human recombinant interleukin-1 beta stimulates glycosaminoglycan production in human synovial fibroblast cultures.
Human recombinant interleukin-1 beta (rIL-1 beta) stimulated glycosaminoglycan (GAG) production in human synovial fibroblast cultures. A dose-dependent increase in GAG production was found, to a maximum of 500%. Increase was detected at doses as low as 1 pg/ml of rIL-1 beta, reached a maximum at 10-100 pg/ml, and was apparent 10 hours after addition of rIL-1 beta. Stimulation of GAG was always accompanied by increased accumulation of prostaglandin E (PGE) in culture media and by increased collagenase production in approximately one-half the experiments. Indomethacin (5 micrograms/ml) completely inhibited PGE stimulation by rIL-1 beta, but only partially inhibited that of GAG overproduction and had no effect on collagenase production. Hydrocortisone (2 micrograms/ml) inhibited stimulation of all 3 parameters. Stimulation of hyaluronate in synovial cultures prevailed over that of sulfated GAG, which occurred to a lesser extent. Our results support earlier suggestions that interleukin-1 is a major active mononuclear cell factor that is capable of inducing profound changes in connective tissue cell function.
Cells, Cultured↗
Effect of synthetic calcium pyrophosphate and hydroxyapatite crystals on the interaction of human blood mononuclear cells with chondrocytes, synovial cells, and fibroblasts.
Synthetic calcium pyrophosphate dihydrate crystals and, to a lesser extent, synthetic hydroxyapatite crystals increased the amount of interleukin-1/mononuclear cell factor released by human blood monocytes, as measured by collagenase and prostaglandin E2 production by rabbit chondrocytes, human dermal fibroblasts, and adherent rheumatoid synovial cells. The same crystals also directly induced collagenase and prostaglandin E2 secretion by rabbit chondrocytes, and potentiated the action of interleukin-1/mononuclear cell factor on chondrocytes. These mechanisms may be important in the pathogenesis of the destructive arthropathies associated with these crystals.
Animals↗
Systemic administration of etretin increases epidermal interleukin I in the rat.
We have studied the effect of systemic administration of etretin (Ro 10-1670) on the epidermal interleukin I (ILI) pool in the rat. Hairless rats were given varying doses of etretin intraperitoneally for 21 days, or a fixed dose for 2, 8 and 16 days. Abdominal skin was taken and processed for light microscopy, autoradiography (using [3H]-thymidine) and ILI assays. ILI was assayed in supernatants of epidermal extracts by both the lymphocyte activating factor (LAF) assay and the stimulation of prostaglandin E2 (PGE2) release from dermal fibroblasts. A significant increase in both LAF and PGE2 stimulatory activities was found during etretin administration. After 21 days' treatment with varying doses there was a two- to three-fold increase as compared to the controls, with a peak at 2 and 5 mg/kg. At a fixed dose a two-fold increase was found after 2 days and a three- to four-fold increase after 16 days; normal pretreatment values were restored 16 days after cessation of etretin. This is the first demonstration in vivo that a retinoid can modulate ILI content in a tissue. As epidermal ILI has been found to be decreased in psoriasis, its modulation by retinoids might have therapeutic significance.
Acitretin↗
Interleukin-1 decreases renal sodium reabsorption: possible mechanism of endotoxin-induced natriuresis.
Administration of pyrogen or endotoxins such as Escherichia coli lipopolysaccharide can elicit a marked increase in urinary sodium excretion. This response occurs without any elevation in the filtered load of sodium and it does not appear to be prostaglandin mediated. The various effects produced by endotoxins appear to have interleukin-1 as a common mediator. In the present work, we have studied whether human recombinant interleukin-1 beta (hrIL-1) could affect the renal handling of sodium and thus, could be implicated in natriuretic response to pyrogens or endotoxins. We observed that hrIL-1 intravenously injected into conscious rats provokes a marked increase in sodium excretion. This natriuretic response was not associated with any increase in glomerular filtration rate (clearance of [3H]inulin), nor was it accompanied by significant changes in the urinary excretion of potassium, calcium, or inorganic phosphate. The only concomitant alteration was a decrease in urinary pH. Pretreatment with indomethacin abolished the effect of hrIL-1 on urinary pH but did not modify the natriuretic response. In conclusion, hrIL-1 elicits a selective decrease in tubular sodium reabsorption, which does not appear to involve a change in prostaglandin synthesis. This observation strongly suggests that interleukin-1 could be a key mediator in endotoxin-induced natriuresis.
Absorption↗
Limited effects of recombinant human and murine interleukin 1 and tumour necrosis factor on production of acute phase proteins by cultured rat hepatocytes.
Albumin, fibrinogen, alpha 1-acid glycoprotein and cysteine proteinase inhibitor were determined by electroimmunoassay in the media of primary cultures of rat hepatocytes exposed to dialysed supernatants of rat, mouse and human macrophages or to recombinant human and murine interleukin 1 and tumour necrosis factor. Recombinant cytokines in the range of 1 to 1000 ng/ml caused only reduction of albumin synthesis and slight stimulation of alpha 1 acid glycoprotein production while crude preparations of macrophage cytokines elicited typical acute phase response. The results suggest that interleukin 1 or tumour necrosis factor are not likely the principal mediators responsible for the direct stimulation of normal rat hepatocytes to acute phase protein synthesis.
Animals↗
Expression of human IL 1 alpha and beta messenger RNAs and IL 1 activity in human peripheral blood mononuclear cells.
The macrophage-derived lymphokine interleukin 1 (IL 1) plays a critical role in modulating immune (cellular and humoral) and nonimmune responses. For example, the relative expression of IL 1 alpha and beta under various states may be crucial to the success of the immune system in response to infection. Until recently, a comparative study of IL 1 mRNA expression and IL 1 biological activity was not possible. We have cloned both IL 1 alpha and beta cDNAs and employed them as probes in Northern blot analysis to determine in mitogen-stimulated peripheral blood mononuclear cells the steady-state expression of their cognate mRNAs with respect to IL 1 activity. IL 1 was determined by the lymphocyte-activating factor (IL 1/LAF) and the mononuclear cell factor (IL 1/MCF) activities. In lectin-stimulated PBMC, maximum cell-associated activities whereas detected at 12 and 24 hr after stimulation whereas maximum extracellular activities appeared between 24-48 hr. In the same cultures, the kinetics of IL 1 mRNA steady-state expression were determined by Northern gel blot analysis with IL 1 alpha and beta cDNA probes. IL 1 mRNAs were undetectable in noncultured freshly isolated PBMC (time zero). Both IL 1 mRNAs appeared as early as 4 hr after lectin stimulation as did IL 1 beta mRNA in unstimulated cultures. Both IL 1 alpha and beta mRNA steady-state levels were barely detectable by 48 hr. At all time points, IL 1 mRNA levels were considerably lower in unstimulated cultures. IL 1 beta mRNA was always considerably more abundant than IL 1 alpha mRNA. The less abundant IL 1 alpha mRNA showed a decrease in its stead-state levels prior to the reduction in the levels of IL 1 beta mRNA. TNF alpha activity and mRNA were not detected under these culture conditions. Poly(A) + RNA injected into Xenopus oocytes revealed that the Northern blot detected IL 1 mRNAs were biologically active. To understand the precise nature of IL 1 in immune and nonimmune events, we felt it necessary to first study the kinetics of IL 1 mRNA steady-state levels with respect to its cell-associated and extracellular biological activities. The data presented here may allow for a better understanding of the etiology of various immune and nonimmune responses that are modulated through the expression of IL 1.
Animals↗
[Protein mapping of normal circulating cells: lymphocytes and monocytes].
Purified lymphocyte and monocyte populations were obtained from peripheral blood cells by ficoll-hypaque gradient and elutriation in different normal individuals. The two types of mononuclear cells were then analyzed by 2-dimensional gel electrophoresis. More than 1,000 spots were detected by our computer system and analyzed for each cell type. Automatic picture comparison showed a typical pattern for the two different populations with excellent reproducibility.
Blood Protein Electrophoresis↗
Purification and characterization of human interleukin-1 beta expressed in recombinant Escherichia coli.
The high-level expression of human interleukin-1 beta in Escherichia coli is described. The protein contributes about 12% of the total cell protein and is associated with the soluble cytoplasmic fraction of the cell. A method for the purification of the protein is given which is based on anion- and cation-exchange chromatographies. The isolated protein, shown to be homogeneous by several analytical methods, has been characterized by amino acid analysis, N- and C-terminal sequence analysis and analytical centrifugation. The protein is biologically active as demonstrated by two different in vitro assays, namely, the mononuclear cell factor (IL-1/MCF) assay and lymphocyte activating factor (IL-1/LAF) assay. The specific activities determined with the IL-1/MCF and IL-1/LAF assays, are 2 X 10(7) and 4 X 10(7) units mg-1, respectively.
Amino Acid Sequence↗
[Properties of inflammatory cells in broncho-alveolar lavage in pulmonary fibrosis].
Bronchoalveolar lavage in alveolitis and fibrotic lung diseases serves mainly (1) as a tool facilitating diagnosis and prognosis, and (2) to provide insight into the pathophysiology of tissue destruction and fibrotic processes. The interaction between macrophages, lymphocytes, polymorphonuclear leukocytes and fibroblasts is in part controlled by polypeptides (cytokines), some of whose structures and genes are well characterized. The macrophage seems to be a key mediator between the immune and non-immune cells. The major cytokines produced by macrophages which may play a role in fibrotic processes are interleukin-1, tumor necrosis factor/cachectin, platelet-derived growth factor, and interferons alpha and beta. Once it becomes possible in vivo to quantify cellular activation and production of these cytokines, these diseases will be easier to monitor and more rational therapeutic approaches will be found.
Bronchi↗