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Interleukin-1 (IL-1) is a factor that can induce proliferation of murine T lymphocytes1,2 and can elicit a variety of other biological responses. These include bone resorption3, fibroblast proliferation4, acute phase protein release from... more
Interleukin-1 (IL-1) is a factor that can induce proliferation of murine T lymphocytes1,2 and can elicit a variety of other biological responses. These include bone resorption3, fibroblast proliferation4, acute phase protein release from hepatocytes5, cartilage breakdown6 and fever7. This spectrum of activities is consistent with a role for IL-1 as a mediator of inflammation. Recently, sequence data have shown that there are at least two members of the IL-1 family; these distantly related proteins have been termed IL-1alpha and IL-1beta8-11. We have found previously that both murine T cells and fibroblasts possess a relative molecular mass (Mr) ~80,000 (80K) plasma membrane receptor for human IL-1beta12,13. We show here that the receptor for IL-1alpha on both murine and human cells is identical to that for IL-1beta. This result raises the issue of what separation, if any, there might be between the biological activities of IL-1alpha and IL-1beta.
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We have purified human interleukin 1 (IL-1) to homogeneity by a simplified procedure that results in excellent yields of pure material that retains a high level of biological activity. IL-1, secreted by human peripheral blood macrophages... more
We have purified human interleukin 1 (IL-1) to homogeneity by a simplified procedure that results in excellent yields of pure material that retains a high level of biological activity. IL-1, secreted by human peripheral blood macrophages that have been stimulated with Staphylococcus aureus, was purified by ion exchange chromatography and affinity chromatography on Procion Red agarose. The pure protein has a specific activity of 3.2 X 10(8) U/mg in the thymocyte mitogenesis assay, and is pyrogenic. No molecular weight heterogeneity was observed, in contrast to findings for mouse IL-1 and earlier reports of human IL-1. Purified IL-1, as analyzed by two-dimensional electrophoresis/electrofocusing gels, exhibited a series of charged species with isoelectric points ranging from 6.0 to 4.9, all with a molecular weight of approximately 17,500. Amino acid analysis indicated an abundance of acidic residues, in agreement with the low isoelectric points. There is little or no cysteine in the m...
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ABSTRACT The substrate specificity of the protease which generates mature human interleukin-1 beta (IL-1 beta) from pro-interleukin-1 beta was investigated using synthetic peptide substrates and recombinant pro-IL-1 beta. The requirement... more
ABSTRACT The substrate specificity of the protease which generates mature human interleukin-1 beta (IL-1 beta) from pro-interleukin-1 beta was investigated using synthetic peptide substrates and recombinant pro-IL-1 beta. The requirement of an L-aspartate in the P-1 position was confirmed together with the need for a small hydrophobic residue in the P-1' position (Gly or Ala). It was shown that the enzyme can tolerate conservative substitutions in the P-2 and P-2' positions. We found little difference in the enzyme's ability to cleave denatured and native pro-IL-1 beta, indicating that tertiary structure recognition is not involved in binding. The enzyme did, however, require a peptide of more than six amino acids for cleavage to occur. These results conclusively demonstrate the unusual specificity of this protease.
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Somatostatin-like immunoreactivity (SLI) has been demonstrated by radioimmunoassay (RIA) in rat serum using an antiserum specific for somatostatin and cross-reacting maximally with the biologically important area on the peptide. The RIA... more
Somatostatin-like immunoreactivity (SLI) has been demonstrated by radioimmunoassay (RIA) in rat serum using an antiserum specific for somatostatin and cross-reacting maximally with the biologically important area on the peptide. The RIA has a sensitivity of 35 pg/ml. SLI dilutes in parallel with synthetic somatostatin standard in the RIA and shows characteristics similar to synthetic somatostatin on Sephadex G-25 (f) gel chromatography eluting largely as a single peak with 1 M acetic acid. Significant regional differences in serum SLI are present. A positive gradient was found in paired samples from aorta (mean+/-SEM, 0.304+/-0.024 ng/ml) and portal vein (0.495+/-0.047 ng/ml) consistent with the known presence of somatostatin in gut and pancreas, and a negative gradient was noted between paired samples from portal vein (0.523+/-0.076 ng/ml) and hepatic vein (0.290+/-0.048 ng/ml) indicating hepatic clearance. No significant differences were demonstrated between aorta and confluence of cerebral venous sinuses or between aorta and inferior vena cava (IVC). After intragastric glucose, a significant and marked elevation of portal SLI was observed, maximal at 5 min (0.416+/-0.137 vs. 1.55+/-0.30 ng/ml at 5 min). A significant biphasic elevation of portal SLI also occurred after intravenous glucose. After both routes of glucose administration, the patterns of portal SLI followed closely those of portal glucose and insulin. By contrast, IVC SLI failed to reflect these changes.Thus, SLI in the rat shows chromatographic similarity with synthetic somatostatin. Regional differences in serum levels are marked; the highest concentrations being found in the portal venous effluent of pancreas and gut. Furthermore, glucose causes elevation of portal SLI in a pattern similar to portal insulin and glucose and without concomitant elevation in IVC. This differential elevation of SLI after glucose is consistent with a hormonal action within the portal system as a direct effect of somatostatin on the liver has previously been demonstrated. In addition, the liver is important in the clearance of portal SLI, possibly to prevent extraportal effects in response to gut and pancreatic stimulation. Finally, it is clear that regional sampling of serum for SLI measurement may be critical in the investigation of the putative physiological roles for somatostatin.
Research Interests: Somatostatin, Glucose, Blood Glucose, Insulin, Glucagon, and 7 moreLiver, Animals, Hormones, Male, Rats, Clinical Investigation, and Radioimmunoassay
Somatostatin-like immunoreactivity (SLI) was measured in extracts of gastric antrum, colon, pancreas, and central nervous system, as well as in unextracted portal and inferior vena caval serum from fed, 15-h-fasted, and 72-h-fasted rats.... more
Somatostatin-like immunoreactivity (SLI) was measured in extracts of gastric antrum, colon, pancreas, and central nervous system, as well as in unextracted portal and inferior vena caval serum from fed, 15-h-fasted, and 72-h-fasted rats. No differences were found in SLI in the central nervous system of the three groups. However, striking variations were found in the gastrointestinal tract and pancreas; the antrum, colon, and pancreas of 15-h-fasted rats contained the least SLI, the content being significantly elevated in these three areas after feeding and after a 72-h fast. Portal serum levels were highest after feeding but lowest in 72-h-fasted rats, in spite of high intestinal and pancreatic SLI content in both. These tissue and serum differences suggest a physiologic role for SLI in nutrient homeostasis not only at tissue level, but also putatively as a hormone in the portal system.
Research Interests: Diabetes, Somatostatin, Brain, Fasting, Animals, and 4 moreSpinal Cord, Male, Rats, and Time Factors
A calcium-dependent release of immunoreactive somatostatin from rat spinal cord in vitro in response to two depolarising stimuli (60 mM KCl and 75 micrometer veratrine) has been demonstrated. Released somatostatin immunoreactivity... more
A calcium-dependent release of immunoreactive somatostatin from rat spinal cord in vitro in response to two depolarising stimuli (60 mM KCl and 75 micrometer veratrine) has been demonstrated. Released somatostatin immunoreactivity comprised 0.53% of total tissue content, showed parallelism when serial dilutions were compared to the immunoassay dose-response curve and eluted similarly to synthetic somatostatin on Sephadex G-25 (f) chromatography. These results provide further evidence for a neurotransmitter or neuromodulator role for somatostatin in mammalian spinal cord.
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Interleukin-1 (IL-1) is a factor that can induce proliferation of murine T lymphocytes1,2 and can elicit a variety of other biological responses. These include bone resorption3, fibroblast proliferation4, acute phase protein release from... more
Interleukin-1 (IL-1) is a factor that can induce proliferation of murine T lymphocytes1,2 and can elicit a variety of other biological responses. These include bone resorption3, fibroblast proliferation4, acute phase protein release from hepatocytes5, cartilage breakdown6 and fever7. This spectrum of activities is consistent with a role for IL-1 as a mediator of inflammation. Recently, sequence data have shown that
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Research Interests: Neurochemistry, Calcium, Somatostatin, Hypothalamus, Animals, and 4 moreMale, Potassium, Rats, and Neurosciences
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Research Interests: Kinetics, Lymphoma, Cell line, Humans, Mice, and 15 moreAnimals, Fibroblast Growth Factor, Model System, Experimental Medicine, Biological activity, Bovine Serum Albumin, Membrane Protein, Polyacrylamide Gel Electrophoresis, Epidermal Stem Cells, Plasma Membrane, Bone Resorption, Interleukin, Phosphate Buffer Saline, Inflammatory response, and Cell Membrane
The MCR and t1/2 of D-Trp6 LRH, a potent analog of LRH, were compared to those of exogenous LRH. Studies were performed on eight normal subjects during and after cessation of a constant infusion of D-Trp6 LRH and LRH. The D-Trp6 LRH and... more
The MCR and t1/2 of D-Trp6 LRH, a potent analog of LRH, were compared to those of exogenous LRH. Studies were performed on eight normal subjects during and after cessation of a constant infusion of D-Trp6 LRH and LRH. The D-Trp6 LRH and LRH were quantitated individually by sensitive and specific RIAs which did not cross-react with the other peptide infused or fragments of the degraded peptides. High performance liquid chromatography of plasma from a patient infused with D-Trp6 LRH alone yielded one peak, which coeluted with D-Trp6 LRH. The kinetics of peptide clearance were biphasic, with a rapid and a slow component of elimination. The t1/2 of the rapid component of D-Trp6 LRH clearance was 18.7 +/- 1.8 (SEM) min. This was significantly longer (P less than 0.001) than the t1/2 for the LRH of 7.8 +/- 1.1 min. The MCRs for D-Trp6 LRH and LRH were 503.4 +/- 196.4 and 1766.6 +/- 404.3 ml/min, respectively (P less than 0.01). The longer t1/2 of D-Trp6 LRH compared to that of LRH reflects the slower clearance, which is probably due to a decreased rate of degradation. These findings indicated that the enhanced bioactivity of D-Trp6 LRH is in part due to a decreased rate of degradation.
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In streptozotocin diabetes in the rat, growth hormone release-inhibitory hormone-like immunoreactivity (GHRIH-LI) content of pancreas, gastric antrum and colon was increased. Insulin therapy significantly lowered the increased pancreatic... more
In streptozotocin diabetes in the rat, growth hormone release-inhibitory hormone-like immunoreactivity (GHRIH-LI) content of pancreas, gastric antrum and colon was increased. Insulin therapy significantly lowered the increased pancreatic GHRIH-LI content but did not affect that of the gastric antrum and colon at the dosage used. The relevance of these findings in relation to pancreatic and gastrointestinal function in diabetes awaits clarification.
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Growth hormone (GH) has been shown to cause a dose-dependent increase in the release of immunoreactive somatostatin from the rat hypothalamus in vitro, thus providing further evidence that GH may be involved in a "short... more
Growth hormone (GH) has been shown to cause a dose-dependent increase in the release of immunoreactive somatostatin from the rat hypothalamus in vitro, thus providing further evidence that GH may be involved in a "short loop" feedback, controlling its own secretion via hypothalamic somatostatin release.