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Biomedical subjects

G W Duff

Publications and source records attributed to G W Duff.

At least 109 records · Page 6Linked to original sources
PubMed1990

Absence of correlations between indices of systemic inflammation and synovial fluid interleukin 1 (alpha and beta) in rheumatic diseases.

There are two forms of the cytokine interleukin 1 (IL1), produced by two distinct genes encoding a neutral (IL1 beta) and an acidic (IL1 alpha) peptide. They have powerful pro-inflammatory, immunopotentiating, catabolic and arthritogenic properties in vivo and have been implicated in the pathogenesis of rheumatic diseases. In this study, using specific immunoassays, we have measured both IL1 alpha and IL1 beta levels in synovial fluids (SF) from a large number of patients with different rheumatic diseases. Biologically significant levels of both cytokines were found in SF from patients with different forms of arthritis, but no correlations were found with any of the measures of disease activity that we tested. We also describe the presence in joint exudates of biological inhibitor(s) that neutralize IL1-induced T-cell activation. This is the first report of IL1 alpha and IL1 beta measurements in the same synovial exudates and also of the comparison of local levels of these cytokines with conventional indices of systemic inflammation.

Arthritis↗
PubMed1990

Interleukin 1 beta in synovial fluid is related to local disease activity in rheumatoid arthritis.

Interleukin 1 beta (IL-1 beta) is a polypeptide with pro-inflammatory and immunopotentiating effects in vivo and in vitro. With relevance to rheumatoid arthritis (RA) IL-1 augments release of prostanoids, proteinases and oxygen metabolites and is a potent inducer of bone and cartilage resorption. Although high levels of IL-1 have been found in rheumatoid synovial fluids, intra-individual variation in IL-1 production has made it difficult to correlate these levels with disease activity. To overcome this problem we have studied patients with symmetrical and asymmetrical knee joint inflammation. Local disease activity was documented using Ritchie score and joint circumference; IL-1 beta levels were quantitated in synovial fluid by ELISA. In patients with symmetrical joint involvement almost identical levels of IL-1 beta were detected in the right and left knee joints. In contrast, in patients exhibiting asymmetrical knee joint involvement, IL-1 beta levels in the inflamed joints were significantly higher than in the contralateral joints. The study provides further evidence for the role of IL-1 in the pathogenesis of rheumatoid inflammation.

Adult↗
PubMed1990

Interleukin 1: the first interleukin.

The name 'interleukin' and the designation of interleukin 1 (IL-1) derived from the Second International Lymphokine Workshop held in Switzerland in 1979. Since then interest in the original interleukin (IL-1) has increased exponentially as measured by the numbers of publications and meetings. The main reasons for this can be seen in the accompanying centrefold. The perception of IL-1 as a biological mediator in every organ system has attracted scientists from widely different backgrounds into this area and a steady succession of important and often surprising insights into IL-1 biology has ensured that interest has been sustained at a high level. This overview of the biology of IL-1 on the tenth anniversary of its turbulent life has been compiled by Franco di Giovine and Gordon Duff. It is of necessity selective and biased towards human IL-1 and begins with some general points (mainly cautionary) as a backdrop to the centrefold.

Animals↗
PubMed1990

A soluble binding protein specific for interleukin 1 beta is produced by activated mononuclear cells.

Soluble interleukin 1 (IL 1) binding proteins were identified by gel filtration and covalent cross-linking of 125I IL 1 in normal human serum and inflammatory exudate. High molecular weight 125I IL 1 protein complexes occurred with both IL 1 alpha and IL 1 beta, however, high molecular weight binding appeared to be non-specific. One specific IL 1 beta binding protein was observed to elute at approximately 100 kDa on gel filtration when bound to 125I IL 1 beta. This complex migrated as a broad band at 60 kDa when covalently cross-linked and analyzed by SDS-PAGE. The protein did not bind 125I IL 1 alpha and 125I IL 1 beta binding was only displaceable by excess cold IL-1 beta. The production of the specific IL 1 beta binding protein was assessed in a number of cell populations. Unstimulated peripheral blood mononuclear cells (PBMNC) did not produce the binding protein, but stimulation with phytohemagglutinin (PHA) caused production within 24 hr and binding protein levels remained elevated for up to 7 days. Stimulation with lipopolysaccharide (LPS) and IL 1 alpha did not consistently induce synthesis of the binding protein. Ligand-binding studies were performed to compare solubilized EL 4 NOB.1 cell membrane IL 1 receptor (sIL 1R) with semi-purified IL 1 beta binding protein from pooled synovial fluid. The sIL 1R preparation bound ligand with an affinity of 168 pM while the IL 1 beta binding protein bound 125I IL 1 beta with an affinity of 370 pM. This protein may function as an important carrier molecule for IL 1 beta and determine its distribution and kinetics in vivo.

Carrier Proteins↗
PubMed1990

Soluble CD8 in patients with rheumatic diseases.

An ELISA was used to measure soluble CD8 (sCD8) in the sera and synovial fluids (SF) of patients with rheumatic diseases. Patients with rheumatoid arthritis (RA) had raised levels of sCD8 both in their sera and in their SF compared with patients with osteoarthritis and age-matched healthy controls. In individual RA patients, serial serum sCD8 levels initially fell and then rose preceding clinical improvement. In four patients where serum sCD8 levels rose and clinical improvement occurred, subsequent spontaneous decreases of serum sCD8 level preceded increased clinical disease activity by up to 2 weeks. In general, RA SF mononuclear cells (SFMNC) spontaneously produced high levels of sCD8. In contrast, autologous peripheral blood MNC only produced comparable levels after mitogenic stimulation. Incubation of SFMNC with increasing concentrations of human recombinant tumour necrosis factor alpha resulted in a dose-dependent potentiation of sCD8 release into the supernatant. There was an inverse relationship between the ability of SFMNC to release sCD8 and soluble interleukin-2 receptor, indicating that the CD8+ T cell population may play an important immunoregulatory role in RA.

Adult↗
PubMed1990

Serum-soluble interleukin 2 receptor in psoriasis. Failure to reflect clinical improvement.

Interleukin 2 (IL-2) is a T-cell growth factor produced by activated T cells. The cellular receptor for IL-2 is also expressed on activated T cells and one of its component molecules can be shed from the cell and measured as a soluble protein (sIL-2R). Blood levels of sIL-2R can be used to monitor in vivo immune activation and have been shown to correlate with clinical disease activity in conditions such as rheumatoid arthritis and atopic eczema. The present study shows that serum sIL-2R levels are raised in patients with chronic plaque psoriasis. These elevated serum levels were maintained during successful treatment of the skin lesions with topical tar preparations. This is in contrast to atopic eczema where serum sIL-2R levels fall with treatment and may indicate that topical treatment of psoriasis does not correct the underlying state of immune activation, even when resolution of the skin plaques is achieved.

Administration, Cutaneous↗
PubMed1990

In situ hybridisation.

In situ hybridisation of mRNA in tissues or cell preparations is a powerful technique for studying gene expression. When combined with cell phenotyping with monoclonal antibodies it gives insights into the cellular basis of disease in vivo. The technique has also been used widely to identify foreign nucleic acids--for example, bacterial or viral, in host cells. The major disadvantages of this approach in the past have been that it was technically demanding, time consuming, and provided qualitative rather than quantitative results. Now, with the use of non-radioactive probes and improved imaging systems, the full potential of this form of molecular analysis is increasingly accessible and should generate rapid advances in many fields.

Arthritis, Rheumatoid↗
PubMed1989

Soluble interleukin 2 receptor in atopic eczema.

OBJECTIVE: To determine whether serum soluble interleukin 2 receptor concentrations are related to disease activity in atopic eczema. DESIGN: Single cohort longitudinal study with controls. SETTING: Outpatient and general medicine departments in secondary referral centre. PATIENTS: Of 15 patients aged 17-57 with severe atopic eczema, all with acute exacerbations of disease, 13 were admitted to hospital and two treated as outpatients until the skin lesions had resolved or greatly improved. Nineteen controls gave single blood samples. INTERVENTIONS: Daily skin dressing with betamethasone valerate (0.025%) and ichthammol paste and tubular dressings. END POINT: Resolution of or considerable improvement in skin lesions. MEASUREMENTS AND MAIN RESULTS: Enzyme linked immunosorbent assays (ELISA) were used to measure serum soluble interleukin 2 receptor concentrations in blood samples taken on admission, at intervals subsequently, and on discharge. Clinical scores of disease activity were also made. Median concentrations on admission were significantly higher (770 U/ml) in the patients than the controls (300 U/ml). Concentrations fell significantly during treatment. In 25 assessments made at different times in 13 patients serum soluble interleukin 2 receptor concentration correlated significantly (R = 0.73) with clinical disease activity. CONCLUSIONS: Cellular immunopathogenic mechanisms contribute to atopic eczema. Immune activation can be measured in atopic eczema by measurements of soluble interleukin 2 receptor, and this should facilitate assessment of response to treatment.

Acute Disease↗
PubMed1989

Autoregulation of interleukin 1 production.

Interleukin 1 (IL 1) alpha and beta are distinct cytokines with a common receptor on target cells. Both have been implicated in immunity, inflammation and connective tissue metabolism. Their production is stimulated by microbial products and also by other cytokines derived from accessory cells and lymphocytes. Following reports that IL 1 can stimulate its own production, we have tested the effects of recombinant IL 1 on the synthesis and release of IL 1 alpha and beta by human blood mononuclear cells (MNC). We confirmed that autoinduction occurs but report also the novel finding that this effect is very concentration dependent. At some concentrations within the range found in vivo, recombinant IL 1 not only failed to stimulate further IL 1 production but also inhibited the background level of synthesis in 20-h MNC cultures. The negative feedback appears unrelated to prostaglandin E2 and interferon-gamma levels and could not be reproduced by adding transforming growth factor beta. This previously unrecognized autoregulation may be relevant to clinical diseases associated with pathogenic over-production of IL 1.

Animals↗
PubMed1989

Human decidua: a source of interleukin-1.

These studies were conducted to determine whether human decidua produces interleukin-1 in response to bacterial endotoxin. Explants of human decidua were incubated with and without Escherichia coli endotoxin for 20 hours. When tested for interleukin-1-like activity with the D10.G4.1 T-cell bioassay, supernatants from endotoxin-stimulated decidua contained significantly more interleukin-1 activity than did supernatants from unstimulated decidua. This activity could not be attributed to interleukin-2, as determined in the CTLL/2 assay for interleukin-2. Interleukin-1-like activity was due to interleukin-1, as demonstrated by the blockade of this bioactivity with antibodies against interleukin-1: interleukin-1 alpha and interleukin-1 beta. Antibodies against interleukin-1 alpha blocked the activity in five of six cases. In one instance, the bioactivity could be attributed to a mixture of interleukin-1 alpha and interleukin-1 beta. These data demonstrate that human decidua can produce interleukin-1 in response to bacterial endotoxin.

Antibodies↗
PubMed1989

Interleukin 1 in rheumatoid arthritis: potentiation of immune responses within the joint.

Specific immunoassays were used to measure IL-1 peptides in the serum and synovial fluid of patients with rheumatoid arthritis (RA) and in the serum of age-matched healthy controls. Patients with RA had raised levels of both IL-1 beta and IL-1 alpha in their sera compared to controls. Synovial fluid levels of IL-1 beta significantly correlated with immunoreactive IL-2 and soluble IL-2 receptor (sIL-2R). In addition, incubation of synovial fluid MNC with human recombinant (hr) IL-1 caused a dose-dependent increase in the level of sIL-2R in the cell supernatant. Finally, production of IL-1 beta and IL-6 from RA peripheral blood (PB) and synovial fluid (SF) MNC was examined. PBMNC spontaneously produced low levels of IL-1 beta and IL-6 that were augmented by the addition of hr IL-1 alpha. In contrast, SFMNC spontaneously produced high levels of IL-1 beta but only low levels of IL-6, again this production was augmented by the addition of hr IL-1 alpha. Taken together, the data suggests that IL-1 potentiates immune responses within the joint.

Arthritis, Rheumatoid↗
PubMed1988

Soluble IL-2 receptor in rheumatoid arthritis. Correlation with disease activity, IL-1 and IL-2 inhibition.

An ELISA was used to measure soluble IL-2R (sIL-2R) in the sera and synovial fluids of patients with rheumatic diseases. Patients with rheumatoid arthritis had raised levels of sIL-2R both in their sera and in their synovial fluid compared to patients with osteoarthritis and age-matched healthy controls. Mononuclear cells from the synovial fluid of rheumatoid arthritis patients were found to produce spontaneously high levels of sIL-2R which eluted at approximately m.w. 40,000 on gel filtration. In contrast, autologous peripheral blood cells only produced comparable levels upon stimulation with mitogenic lectin. Sequential studies indicated that serum sIL-2R levels were highly correlated with disease activity, indicating that measurement of sIL-2R may be a useful clinical marker in the future. Within the joint, synovial fluid sIL-2R levels correlated significantly with immunoreactive IL-1 beta levels, providing evidence for a role of IL-1 in immune activation in the synovium. In synovial fluids, sIL-2R level also correlated with functional inhibition of IL-2-driven responses in vitro. Furthermore, sIL-2R immunoreactivity in synovial fluid eluted at m.w. 100,000 coeluting with IL-2-inhibitory activity and consistent with a role for sIL-2R in down-regulation of IL-2 responses. The abnormal m.w. may be accounted for by complex formation in the synovial fluid. Given the ability of sIL-2R to bind IL-2, the presence of sIL-2R within the joint may contribute to the well documented "IL-2 defect" seen in rheumatoid arthritis.

Adult↗
PubMed1988

Correlation of plasma interleukin 1 levels with disease activity in rheumatoid arthritis.

The mean plasma level of interleukin 1 beta (IL-1 beta), measured by immunoassay, was significantly higher in 51 patients with rheumatoid arthritis (RA) than in 21 healthy controls of similar age. Further, in the RA group, plasma IL-1 beta correlated positively with Ritchie joint index, pain score, and erythrocyte sedimentation rate and correlated negatively with haemoglobin concentration. In individual patients with active disease who had serial measurements, plasma IL-1 beta also correlated with clinical disease activity. These results support the idea that IL-1 beta has a central role in the pathogenesis of RA.

Adult↗
PubMed1988

Serum interleukin-2-receptor in rheumatoid arthritis: a prognostic indicator of disease activity?

Interleukin-2 (IL-2) is an important growth factor for T lymphocytes. Its effects are mediated by cell surface receptors (IL-2 R) expressed on activated T cells. Receptor protein can be shed from cell membranes and the soluble form (sIL-2 R) is detectable by enzyme linked immunosorbent assay (ELISA). We have studied serial levels of sIL-2 R in the sera of patients with rheumatoid arthritis (RA). In 13 patients with active disease, the mean serum level of sIL-2 R was raised compared to age-matched healthy controls. In 48 samples taken at different times from 13 patients, serum sIL-2 R correlated significantly with Ritchie joint index, duration of early morning stiffness, patient pain score, physician's assessment, erythrocyte sedimentation rate (ESR) and platelet count. In individual patients, serial sIL-2 R serum levels fell with treatment preceding clinical improvement. In four patients where serum sIL-2 R levels fell and clinical improvement occurred, subsequent spontaneous increases of serum sIL-2 R level preceded increased clinical disease activity by up to 2 weeks. Serum sIL-2 R level in RA probably reflects activation of underlying immunopathogenic mechanisms and appears to be an excellent monitor of clinical disease activity. More importantly, a rising level may also predict exacerbation of disease activity.

Adult↗
PubMed1988

Synovial fluid concentrations of interleukin-1 beta and proteoglycans are inversely related.

Interleukin-1 beta (IL-1 beta) and proteoglycans have been quantified by radioimmunoassay (IL-1 beta) and enzyme linked immunosorbent assay (proteoglycans) in synovial fluids and sera from patients with rheumatoid arthritis (RA) and reactive arthritis. All fluids were also tested for their ability to influence proteoglycan metabolism in a cartilage explant culture system. Synovial fluid IL-1 beta concentrations were inversely related to proteoglycan concentrations in samples from both RA and reactive arthritis patients (P less than 0.002 for all patients). There was no statistically significant relation between immunoreactive IL-1 beta concentration and proteoglycan synthesis or degradation in explants cultured in synovial fluid containing medium. Synovial fluid IL-1 beta concentrations were not related to erythrocyte sedimentation rate or joint total leukocyte count. IL-1 beta was not detectable (limit 250 pg/ml) in any unextracted sera. Although it appears likely that IL-1 beta is involved in the inflammatory and degenerative processes in joint disease, our findings indicate that there is no simple positive relationship between immunoreactive levels of this cytokine in synovial fluid and liberation of proteoglycans from articular cartilage as reflected in synovial fluid proteoglycan concentration.

Adult↗