Biomedical subjects

S C Gilman

Publications and source records attributed to S C Gilman.

At least 55 records · Page 3Linked to original sources

PubMed1987

Effects of tilomisole, indomethacin and levamisole on regulation of Epstein Barr virus-induced B cell proliferation by peripheral blood mononuclear cells from normal individuals and patients with rheumatoid arthritis.

When activated in autologous mixed leukocyte reactions (auto-MLR) in vitro, T cells from normal individuals produce a suppressor factor(s) which inhibits the Epstein-Barr virus (EBV)-induced proliferation of normal B cells. In contrast, T cells from patients with rheumatoid arthritis (RA) are deficient in their ability to generate this suppressor factor in auto-MLR. Addition of tilomisole (Wy-18,251; 33(p-chlorophenyl)thiazolo[3,2-a]benzimidazole-2-acetic acid) to the auto-MLR (0.1-100 micrograms/ml) did not alter the production of suppressor activity by normal T cells, but 100 micrograms/ml tilomisole restored to normal the defective factor production by RA T cells. Indomethacin (1 microgram/ml) but not levamisole (0.1-100 micrograms/ml) had a similar effect, which suggests that the action of tilomisole in this system is due to its ability to inhibit prostaglandin biosynthesis. Nonetheless, the ability of tilomisole to down-regulate B cell function may contribute to the compound's antiarthritic activity.

Arthritis, Rheumatoid↗

PubMed1987

Phospholipase A2 activation by interleukin 1: release and metabolism of arachidonic acid by IL 1-stimulated rabbit chondrocytes.

Treatment of rabbit chondrocytes with natural or recombinant human IL 1 results in a dramatic dose-dependent increase in intracellular phospholipase A2 (PLA2) activity and subsequent secretion of this enzyme into the intracellular millieu. PLA2 activity is detectable as early as 1 hr after IL 1 stimulation and is maximal by 24 hr. In the present study, we have characterized more fully the relationship between PLA2 activation and arachidonate metabolism in these cells. IL 1 treatment of chondrocytes which had been prelabeled with [14C]arachidonic acid resulted in an enhanced release of free arachidonic acid identified by thin-layer chromatography. Moreover, the arachidonic acid liberated was subsequently metabolized exclusively to PGE2; no significant increases in the production of 6-keto PGF1 alpha, LTB4, LTC4, 12-HETE or 15-HETE were observed following IL 1 stimulation.

Animals↗

PubMed1987

Immunological abnormalities in rats with adjuvant-induced arthritis--II. Effect of antiarthritic therapy on immune function in relation to disease development.

The effects of the experimental immunomodulatory agent tilomisole (Wy-18,251; (3-(p-chlorophenyl) thiazolo [3,2-a]benzimidazole-2-acetic acid) on disease development and immune function in rats with adjuvant-induced arthritis was assessed in comparison with indomethacin and levamisole. Daily p.o. administration of tilomisole (100-200 mg/kg/day) to M. butyricum-injected rats significantly reduced both edema and bone erosion in the uninjected paw. Moreover, tilomisole treatment restored to normal the diminished Con A-induced proliferative response and IL 2 synthesis observed in spleen cells from arthritic rats, but had no effect on macrophage IL 1 production. In contrast, levamisole treatment (25 mg/kg/day) of arthritic rats improved splenic immune function but did not influence paw edema or bone erosion. Conversely, indomethacin (1 mg/kg/day) significantly reduced paw edema and bone erosion but did not improve the deficient proliferative response or IL 2 synthesis by "arthritic" spleen cells. These results indicate that tilomisole possesses combined antiinflammatory and immunomodulatory activity in adjuvant-arthritic rats which is distinctly different from the effects of either indomethacin or levamisole. Moreover, these data suggest that tilomisole has potential disease-modifying activity in arthritis, which is currently being more closely examined in clinical trials.

Animals↗

PubMed1987

Effect of pressure on the release of radioactive glycine and gamma-aminobutyric acid from spinal cord synaptosomes.

Exposure to high hydrostatic pressure produces neurological changes referred to as the high-pressure nervous syndrome (HPNS). Manifestations of HPNS include tremor, EEG changes, and convulsions. These symptoms suggest an alteration in synaptic transmission, particularly with inhibitory neural pathways. Because spinal cord transmission has been implicated in HPNS, this study investigated inhibitory neurotransmitter function in the cord at high pressure. Guinea pig spinal cord synaptosome preparations were used to study the effect of compression to 67.7 atmospheres absolute on [3H]glycine and [3H]gamma-aminobutyric acid ([3H]GABA) release. Pressure was found to exert a significant suppressive effect on the depolarization-induced calcium-dependent release of glycine and GABA by these spinal cord presynaptic nerve terminals. This study suggests that decreased tonic inhibitory regulation at the level of the spinal cord contributes to the hyperexcitability observed in animals with compression to high pressure.

Animals↗

PubMed1987

Corticosterone response underlying tolerance to stress induced by a gaseous (nitrous oxide) environment.

Conditioned taste aversion (CTA) was demonstrated in rats following a single pairing between ingestion of a novel saccharin solution (CS) and 60 min. inhalation of an 80% N2O2:20% N2O gas mixture (UCS). CTA from a single novel CS-N2O UCS pairing was achieved by methodological improvements including: an inhalation chamber for small animals that achieved complete gas diffusion, an increased UCS duration (60 min. of inhalation) and a decreased CS-UCS interval (1 min.). The increased N2O UCS inhalation probably contributed to CTA, since no duration less than 60 min. of N2O inhalation produced significantly greater plasma corticosterone elevation than 60 min. of N2:O2 inhalation. The hypothesis that CTA is stress-induced was supported, in that plasma corticosterone levels were elevated by N2O inhalation and adrenal catecholamines (CA) were depleted. Further, after 4 N2O pretreatments, which produced partial behavioral tolerance to N2O treatment, plasma corticosterone elevation abated somewhat. However, corticosterone level also was raised by N2:O2 treatment. As a result, abatement of corticosterone elevation cannot account for behavioral tolerance to N2O-induced CTA, though it may be a contributor. Since adrenal CA were depleted by N2O inhalation, this response also might abate and underlie or contribute to behavioral tolerance.

Animals↗

PubMed1987

Activation of rabbit articular chondrocytes by recombinant human cytokines.

Treatment of rabbit articular chondrocytes with 0.5-5 units/ml of recombinant human interleukin-1 (IL-1) induced phospholipase A2 (PLA2) activation, prostaglandin E2 (PGE2) biosynthesis and latent neutral protease secretion by these cells. When normalized on the basis of thymocyte costimulatory activity, the beta (pI 7) form of recombinant IL-1 was about 5-fold more potent than the alpha (pI 5) species, although the maximum response induced by either IL-1 form was similar. Recombinant murine IL-1 was also a potent dose dependent activator of chondrocyte arachidonate metabolism and protease secretion. In contrast to IL-1, neither IL-2 nor tumor necrosis factor alpha (TNF alpha) activated PLA2, PGE2, or neutral protease secretion in these cells and neither of these cytokines inhibited the chondrocyte metabolic response to IL-1. These results provide unequivocal evidence that IL-1 is a potent activator of chondrocyte arachidonate metabolism and hydrolytic protease secretion. That all 3 recombinant IL-1 molecules stimulate chondrocytes and yet share limited sequence homology suggests that an amino acid sequence common to all 3 species is required for chondrocyte activation.

Animals↗

PubMed1986

Interleukin 1 activates phospholipase A2 in rabbit chondrocytes: a possible signal for IL 1 action.

We examined the effects of Interleukin 1 (IL 1) on rabbit articular chondrocytes with particular emphasis on arachidonic acid metabolism in these cells. Articular chondrocytes were isolated from the knee joints of normal New Zealand white rabbits and were cultured in vitro until confluent. Addition of 5 U/ml of purified IL 1 to chondrocytes led to an early increase in cell-associated phospholipase A2 (PLA2; measured by hydrolysis of [14C]arachidonic acid-labeled E. coli). Within 1 hr after IL 1 addition, cell-associated PLA2 activity was increased by more than threefold relative to basal PLA2 activity, and further increases in cellular enzyme activity were observed up to 48 hr of IL 1 treatment. IL 1 stimulation also led to a time- and dose-related release of extracellular PLA2 and PGE2, but IL 1-induced PLA2 and PGE2 secretion occurred after the initial burst of intracellular PLA2 activity. Similar PLA2 and PGE2 responses were also observed when purified human IL 1 or IL 1-containing conditioned medium from LPS-stimulated human monocytes were used, but recombinant IL 2 or IL 3 were inactive. IL 1-induced chondrocyte PLA2 did not release radiolabeled free fatty acid from phosphatidylethanolamine labeled at the C-1 position with [14C]stearic acid, confirming the identity of this enzyme as PLA2. These data, therefore, provide the first direct evidence that IL 1 activates cellular PLA2, and we propose that PLA2 activation may be an early signal that initiates the inflammatory actions of IL 1.

Animals↗

PubMed1986

Effects of pressure on uptake and release of calcium by brain synaptosomes.

Uptake of radioactive calcium from guinea pig brain fractions enriched in synaptosomes could be significantly and reproducibly decreased by exposure to high pressure. Calcium efflux from preloaded synaptosomes was unaffected by pressure exposure. It was hypothesized that the development of pressure-induced encephalopathy may be related to an effect of pressure on the central nervous system calcium transport system.

Animals↗

PubMed1986

Effect of pressure on [3H]GABA release by synaptosomes isolated from cerebral cortex.

High hydrostatic pressure has been shown to produce neurological changes in humans which manifest, in part, as tremor, myoclonic jerks, electroencephalographic changes, and convulsions. This clinical pattern has been termed high-pressure nervous syndrome (HPNS). These symptoms may represent an alteration in synaptic transmission in the central nervous system with the inhibitory neural pathways being affected in particular. Since gamma-aminobutyric acid (GABA) transmission has been implicated in other seizure disorders, it was of interest to study GABAergic function at high pressure. Isolated synaptosomes were used to follow GABA release at 67.7 ATA of pressure. The major observation was a 33% depression in total [3H]GABA efflux from depolarized cerebrocortical synaptosomes at 67.7 ATA. The Ca2+-dependent component of release was found to be completely blocked during the 1st min of [3H]GABA efflux with a slow rise over the subsequent 3 min. These findings lead us to conclude that high pressure interferes with the intraterminal cascade for Ca2+-dependent release of GABA.

Animals↗

PubMed1986

Effects of high pressure on the release of excitatory amino acids by brain synaptosomes.

Excitatory amino acid antagonists have been shown to protect against the hyperexcitability associated with exposure to high pressure. This suggests that these excitatory neurotransmitter substances may play a role in the development of the symptoms of high pressure nervous syndrome (HPNS). Using a superfusion technique, we investigated the effect of exposure to 67.7 ATA of pressure on the release of aspartate and glutamic acid by isolated presynaptic nerve terminals from the guinea pig cerebral cortex. Pressure exposure was found to significantly increase the depolarization-induced release of aspartate by these synaptosomes. On the other hand, compression to 67.7 ATA had no effect on glutamic acid release. These findings suggest that increased aspartate release may be a contributing factor in the etiology of HPNS.

Animals↗

PubMed1985

The antiinflammatory activity of the immunomodulator Wy-18,251 (3-(p-chlorophenyl)thiazolo[3,2-a]benzimidazole-2-acetic acid).

The antiinflammatory activity of the immunomodulatory agent Wy-18,251 (3-(p-chlorophenyl)thiazolo-[3,2-a]benzimidazole-2-acetic acid) was examined using a variety of antiinflammatory, analgesic and antipyretic animal models in comparison to aspirin, levamisole and indomethacin. The acute antiinflammatory and analgesic activity of Wy-18,251 (ED50 = 100-200 mg/kg, p.o.) was similar to aspirin, but in contrast to aspirin Wy-18,251 failed to demonstrate antipyretic activity. Wy-18,251 (10-100 mg/kg, p.o.) also inhibited chronic inflammatory responses in the adjuvant- and collagen-induced arthritis models. Wy-18,251 was a modest inhibitor of prostaglandin biosynthesis but did not inhibit either 5- or 15-lipoxygenase enzymes. Wy-18,251 (up to 480 mg/kg, p.o.) produced little gastrointestinal pathology in 16 h fasted rats. The combined immunomodulatory and antiinflammatory activity of Wy-18,251 suggests that this agent may have therapeutic promise in certain immunoinflammatory diseases including rheumatoid arthritis.

Adjuvants, Immunologic↗

PubMed1985

Immunomodulatory activity of Wy-18,251 (3-(p-chlorophenyl)thiazolo[3,2-a]benzimidazole-2-acetic acid).

The in vitro and in vivo effects of the experimental immunomodulatory agent Wy-18,251 (3-(p-chlorophenyl)thiazolo[3,2-a]benzimidazole-2-acetic acid) were studied in comparison with levamisole and indomethacin. Levamisole (4 mg/kg, i.v.) but not Wy-18,251 (less than or equal to 10 mg/kg, i.v.) enhanced carbon clearance rates in vivo in mice. Both Wy-18,251 and levamisole (100 mg/kg, p.o.) significantly suppressed the symptoms of experimental allergic encephalomyelitis (EAE) in rats injected with spinal cord emulsion, but neither were as effective as tilorone in this model. Wy-18,251 and levamisole (1-100 mg/kg, p.o.) suppressed the in vivo generation of plaque-forming cells (PFC) in mice immunized with sheep red blood cells while indomethacin (9 mg/kg, p.o.) enhanced PFC formation. All 3 agents (10(-5) - 10(-6) M) enhanced the in vitro ovalbumin (OA)-specific and Con A- or PHA-induced proliferative response and Con A-stimulated interleukin 2 (IL-2) synthesis of rat spleen cells. Furthermore, in vivo treatment of rats with 1-10 mg/kg (p.o.) of Wy-18,251 and levamisole but not indomethacin increased the subsequent in vitro mitogen or antigen (OA) responsiveness of spleen cells. None of the drugs (10(-5) - 10(-7) M) influenced the natural killer cell (NK) activity of rat spleen cells when incorporated directly into the 51Cr release NK assay.

Animals↗

PubMed1985

Effects of Wy-18,251 (3-p-chlorophenyl)thiazolo[3,2-a]benzimidazole- 2-acetic acid), levamisole and indomethacin on the generation of murine T suppressor cells in vitro.

In vitro culture of normal BALB/c spleen cells with staphylococcal enterotoxin B (SEB) activates antigen non-specific suppressor T cells (Ts) which can be assayed by their ability to suppress antibody production in a plaque assay. Addition of the experimental immunomodulatory drug Wy-18,251 (10-100 microM) to cultures of spleen cells plus SEB significantly increased Ts activity relative to cultures without the drug. Similar results were obtained with levamisole, but, in contrast, indomethacin (0.1-10 microM) inhibited SEB-induced suppressor cell activity. The ability of Wy-18,251 to augment Ts activity could be therapeutically useful in the treatment of those autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, in which hyperactive B cell function is a characteristic feature.

Animals↗

PubMed1984

Lymphoid abnormalities in rats with adjuvant-induced arthritis. I. Mitogen responsiveness and lymphokine synthesis.

Lewis rats injected in the hind paw with Mycobacterium butyricum develop a severe polyarthritis which shares certain features in common with rheumatoid arthritis in man. Spleen and peripheral blood mononuclear cells from rats with this form of arthritic disease proliferate poorly in vitro in response to concanavalin A (con A), phytohaemagglutinin (PHA), and pokeweed mitogen (PWM). The splenic hyporesponsiveness appears within four days of M. butyricum injection (three to five days prior to the development of detectable arthritis), reaches a peak 16-22 days following injection, and persists for at least 40 days. Buffalo strain rats injected with M. butyricum do not develop arthritis, and their spleen cells respond normally to con A, PHA, and PWM. In response to lipopolysaccharide (LPS) the synthesis of interleukin 1 (IL-1) by spleen or peritoneal macrophages from arthritic Lewis rats equalled or exceeded that of macrophages from normal rats. In contrast splenic T cells from arthritic rats produced reduced amounts of interleukin 2 (IL-2; T cell growth factor) in response to stimulation with PHA or con A. Moreover, con-A-activated spleen cells from arthritic rats failed to bind IL-2 and to respond to this growth factor with increased 3H-TdR uptake as did normal spleen cells. In-vitro treatment of 'arthritic' cells with 10(-5) M indomethacin did not restore to normal their reduced mitogen responsiveness, and spleen cells from normal and arthritic rats were equally sensitive to the inhibitory effects of prostaglandin E2 on con-A-induced proliferative responses. These results indicate that peripheral lymphoid function is compromised in rats with adjuvant-induced arthritis and that this functional deficit is mediated by aberrant synthesis of and response to IL-2 by T cells of arthritic animals.

Animals↗

PubMed1984

Antagonism by taurine of pressure-induced tremor in the guinea pig.

The tremorogenic effect of high pressure was antagonized in guinea pigs by intravenous treatment with taurine in doses of 250 and 500 mg/kg. Also pretreatment with 250 mg/kg taurine suppressed tremor development as evidenced by increased threshold and decreased amplitude. It is hypothesized that antagonism of pressure-induced tremor by taurine may be related to changes in membrane calcium transport.

Animals↗

PubMed1984

Effects of oral aspirin and oxaprozin on the development of lupus-like disease in MRL/1 mice.

We examined the effects of two prostaglandin synthetase inhibitors, aspirin and oxaprozin, on the development of lupus-like disease in MRL/1 mice. Daily oral administration of 100 mg/kg of these compounds over a period of 3 months significantly reduced thymic lymphoid hyperplasia. In addition, aspirin but not oxaprozin significantly lowered total lymphocyte counts in the peripheral blood. Other drug-related changes, including reduced hyperplasia in the spleen and lymph nodes and an improvement in kidney vasculitis by aspirin, did not reach statistical significance. Neither aspirin nor oxaprozin influenced the circulating levels of anti-ds DNA antibodies or the severity of kidney glomerulonephritis. While the overall effects of these cyclooxygenase inhibitors were not dramatic, the results do indicate that further studies are warranted to determine the precise therapeutic role, if any, for PG-synthetase inhibitors in lupus-like disease.

Administration, Oral↗

PubMed1984

Lymphokines in immunological aging.

One consequence of the natural aging process is a continual, often severe decline in immune function. In this review, evidence is presented that supports the hypothesis that the age-related diminution in immune function is due, at least in part, to aberrant synthesis of, or response to, certain immunoregulatory lymphokines that play an essential role in immunological responses. It is suggested that pharmacological agents that modulate lymphokine synthesis and/or responsiveness may restore the immunoregulatory imbalance observed in aging and other autoimmune and immunodeficiency disorders.

Aging↗

PubMed1983

Lateral mobility and capping of rat lymphocyte membrane proteins.

Surface immunoglobulin (SIg), RT1 (rat histocompatibility proteins) and thy-1 present on rat lymphocytes cap with similar kinetics and to the same extent, the only difference being the antibody requirement. SIg requires one cross-linking antibody to induce capping, while RT1 and thy-1 require two antibodies. Fluorescence recovery after photobleaching experiments show that there is heterogeneity in the diffusion characteristics of lymphocyte membrane proteins. SIg is relatively immobile when labeled by Fab' and is immobilized by F(ab')2. RT1 diffuses 2.7 times as fast as SIg and the mobile fraction of RT1 is greater. When RT1 is cross-linked by relatively low concentrations of F(ab')2 its mobility is about the same as that of SIg. When the concentration of F(ab')2 is increased, RT1 is immobilized. Thy-1 diffuses faster than SIg and has a higher mobile fraction. When thy-1 is labeled with F(ab')2 it remains mobile and is immobilized when a second antibody layer is added. The relative order of mobility is thy-1 much greater than RT1 greater than SIg.

Animals↗