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Biomedical subjects

M Tsang

Publications and source records attributed to M Tsang.

At least 37 records · Page 2Linked to original sources
PubMed1995

Direct evidence of a heterotrimeric complex of human interleukin-4 with its receptors.

The mode of binding of interleukin-4 (IL-4) to its two known receptors, specific receptor IL-4R and a shared receptor gamma c, was investigated using gel filtration and gel electrophoresis. A ternary complex between IL-4 and the soluble domains of the two receptors was shown to exist in solution. The association constant between gamma c and the stable complex of IL-4/sIL-4R is in the millimolar range, making the ternary complex a feasible target for crystallization studies.

Amino Acid Sequence↗
PubMed1995

Tumor necrosis factor-alpha mediates the release of bioactive transforming growth factor-beta in murine microglial cell cultures.

Tumor necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta produced by glial cells have been proposed bo play a role in various neurodenegerative diseases. The interaction of these two cytokines, however, is unknown. We tested the hypothesis that the TNF-alpha released from lipopolysaccharide (LPS)-treated murine microglial cells would stimulate the release of TGF-beta, which in turn would control TNF-alpha production. Treatment of murine microglial cell cultures with LPS resulted in an acute release of TNF-alpha (peak by 8 hr) followed by delayed release of bioactive TGF-beta (peak by 48 hr). Anti-TNF-alpha antibody significantly inhibited LPS-stimulated TGF-beta production, suggesting the involvement of TNF-alpha in TGF-beta production. Also, exogenous TNF-alpha induced in a dose-dependent fashion microglial cell expression of TGF-beta 1 mRNA and release of TGF-beta. Exogenous TGF-beta, on the other hand, suppressed LPS-stimulated TNF-alpha release. These findings suggest an autoregulation of microglial cell TNF-alpha production by TGF-beta which may limit inflammation-associated brain injury.

Animals↗
PubMed1995

The role of shared receptor motifs and common Stat proteins in the generation of cytokine pleiotropy and redundancy by IL-2, IL-4, IL-7, IL-13, and IL-15.

To understand the molecular bases for cytokine redundancy and pleiotropy, we have compared the Stat proteins activated in peripheral blood lymphocytes (PBLs) by cytokines with shared and distinct actions. Interleukin-2 (IL-2) rapidly activated Stat5 in fresh PBL, and Stat3 and Stat5 in preactivated PBL. IL-7 and IL-15 induced the same complexes as IL-2, a feature explained by the existence of similar tyrosine-phosphorylated motifs in the cytoplasmic domains of IL-2R beta and IL-7R that can serve as docking sites for Stat proteins. IL-13 Induced the same complexes as IL-4, a finding explained by our studies implicating IL-4R as a shared component of the receptors. These studies demonstrate that a single cytokine can activate different combinations of Stat proteins under different physiological conditions, and also indicate two mechanisms by which distinct cytokines can activate the same Stat protein.

Amino Acid Sequence↗
PubMed1995

Activity of combinations of dapsone, rifampin, minocycline, clarithromycin, and sparfloxacin against M. leprae-infected mice.

In these studies we evaluated the activity of low levels of five antimicrobials against Mycobacterium leprae-infected mice when administered singly and in all possible two- and three-drug combinations. Antibiotics studied were: dapsone (D) 0.0001% in the diet, rifampin (R) 20 mg/kg by gavage once monthly, minocycline (M) 0.004% in the diet, clarithromycin (C) 0.001% in the diet, and sparfloxacin (S) 5 mg/kg by gavage five times weekly. Singly each agent was found bacteriostatic (D + R) or partially bactericidal (M, C, and S) but not fully bactericidal. All 10 two-drug regimens were found at least bacteriostatic, 2 being "partially bactericidal" and 4 being "fully bactericidal." Of the 10 three-drug regimens, 9 were found "fully bactericidal" and the other "partially bactericidal." We conclude that combinations of antibiotics active against M. leprae are generally additive in combination.

Animals↗
PubMed1994

Vaccination with pure Mycobacterium leprae proteins inhibits M. leprae multiplication in mouse footpads.

In this study, we evaluated vaccination with a number of purified, as well as recombinant, Mycobacterium leprae proteins for protective efficacy in mice. BALB/c mice were immunized intradermally with various native somatic (purified) or recombinant M. leprae proteins and their synthetic polypeptides emulsified in Freund's incomplete adjuvant. The protective efficacy of these preparations was assessed by enumeration of bacilli in the footpads of mice challenged with viable M. leprae 1 to 2 months following immunization. Protection was afforded by the purified and recombinant 10-kDa M. leprae cytoplasmic heat shock protein, the recombinant cell wall-associated 65-kDa M. leprae heat shock protein, and to a lesser extent, the purified 28-kDa M. leprae cytoplasmic protein (superoxide dismutase). Vaccination with either the purified or recombinant 35-kDa M. leprae cell membrane protein, the synthetic 27-amino-acid N-terminal peptide of the 10-kDa protein, the recombinant 18-kDa M. leprae protein, or the purified 22-kDa cell membrane protein was ineffective. When the interval between immunization and challenge was increased to 6 months, the purified 10-kDa M. leprae protein and the recombinant 65-kDa M. leprae protein lost vaccine efficacy, while a sodium dodecyl sulfate-soluble protein fraction of the M. leprae cell wall (soluble proteins), as had been found previously, continued to protect, suggesting that multiple M. leprae protein epitopes are critical for solid vaccine protection.

Animals↗
PubMed1994

Efficacy of minocycline in single dose and at 100 mg twice daily for lepromatous leprosy.

A clinical trial of minocycline in a total of 10 patients with previously untreated lepromatous leprosy was conducted in order to evaluate the efficacy of a single, initial, 200-mg dose and 100 mg twice daily of minocycline for a total duration of up to 3 months. Patients improved remarkably quickly. Although single-dose therapy did not result in a significant killing of Mycobacterium leprae, viable M. leprae were cleared from the dermis regularly by 3 months of twice-daily therapy, a rate similar to that achieved by minocycline 100 mg once daily. Because more side effects were noted herein than previously with 100 mg daily, we recommend that minocycline, when applied, be administered at 100 mg daily to leprosy patients.

Adolescent↗
PubMed1994

Priming effect of morphine on the production of tumor necrosis factor-alpha by microglia: implications in respiratory burst activity and human immunodeficiency virus-1 expression.

Opiates alter a variety of functional activities of the somatic immune system; within the central nervous system, however, their effects on immune responses are unknown. In the present study, we investigated the effect of morphine on the release of tumor necrosis factor (TNF)-alpha from murine neonatal microglia. Microglial cell cultures did not release TNF-alpha when incubated with morphine alone; however, an enhanced (P < .01) release of TNF-alpha was observed when cultures were first primed with morphine for 24 h and then stimulated with lipopolysaccharide. A bell-shaped dose-response curve was observed for the priming effect of morphine; maximal enhancement of TNF-alpha release (310 +/- 15% of control) was detected at a concentration of 10(-10) M morphine. Pretreatment of microglia for 30 min with opioid receptor antagonists (i.e. naloxone and beta-funaltrexamine) completely blocked the priming effect of morphine. In addition, morphine treatment amplified (P < .01) the priming effect of lipopolysaccharide on phorbol myristate acetate-triggered superoxide anion production by microglial cell cultures, and this effect was abrogated (P < .01) by anti-TNF-alpha antibody. Furthermore, culture supernatants derived from microglial cell cultures that had been treated with morphine before stimulation with lipopolysaccharide had an increased capacity to upregulate human immunodeficiency virus-1 expression in the latently infected promonocytic clone U1. This effect was also blocked by anti-TNF-alpha antibody. These findings suggest that morphine primes microglia for enhanced production of TNF-alpha which could alter several functional activities of these cells within the brain.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Effective vaccination of mice against Mycobacterium leprae with density-gradient subfractions of soluble M. leprae proteins: clues to effective protein epitopes.

It had previously been discovered that intradermal mouse vaccination with a protein fraction of Mycobacterium leprae (called soluble proteins) in Freund's incomplete adjuvant (FIA) resulted in consistent and long-lived protection against M. leprae multiplication from subsequent viable footpad challenges. In this study certain density-gradient subfractions of this soluble protein, but not others, in FIA afforded vaccine protection. The results of this study suggest which M. leprae proteins may be involved in protective immunity, particularly 1-3 kD, 10 kD, 65 kD, and those of higher molecular weight.

Animals↗
PubMed1993

Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor.

The interleukin-2 receptor gamma chain (IL-2R gamma) is a necessary component of functional IL-2 receptors. IL-2R gamma mutations result in X-linked severe combined immunodeficiency (XSCID) in humans, a disease characterized by the presence of few or no T cells. In contrast, SCID patients with IL-2 deficiency and IL-2-deficient mice have normal numbers of T cells, suggesting that IL-2R gamma is part of more than one cytokine receptor. By using chemical cross-linking, IL-2R gamma was shown to be physically associated with the IL-7 receptor. The presence of IL-2R gamma augmented both IL-7 binding affinity and the efficiency of internalization of IL-7. These findings may help explain the defects of XSCID. Given its role in more than one cytokine receptor system, the common gamma chain (gamma c) is proposed as the designation for IL-2R gamma.

Animals↗
PubMed1992

Effects of swimming exercise on the pathogenesis of acute murine Toxoplasma gondii Me49 infection.

The effects of swimming exercise on the pathogenesis of acute murine toxoplasma infection were studied. Swimming (45 min/day) initiated on the day of inoculation with the avirulent Me49 strain of Toxoplasma gondii did not alter survival of infected mice. At a later stage of infection, daily swimming appeared to promote the recovery of appetite and weight gain. Immune activation was apparent in toxoplasma-infected mice, and swimming blunted splenic enlargement but not the respiratory burst activity of peritoneal exudate cells. Infection caused a significant elevation of serum tumor necrosis factor (TNF) levels which was attenuated by a daily swimming program. These data show that swimming exercise is not deleterious to mice acutely infected with T. gondii Me49 and that the more rapid recovery in exercised mice is associated with reduced serum TNF levels.

Acute Disease↗
PubMed1992

Activities of various quinolone antibiotics against Mycobacterium leprae in infected mice.

Previously, pefloxacin and ofloxacin were found to be active against Mycobacterium leprae in vitro, in experimental animals, and in clinical trials of lepromatous leprosy patients. In this study, we compared certain more recently developed fluoroquinolones (lomefloxacin, PD 124816, WIN 57273, temafloxacin, and sparfloxacin) with pefloxacin and ofloxacin in M. leprae-infected mice at doses of 50, 150, and 300 mg/kg given five times weekly. All seven of the fluoroquinolones studies were active against M. leprae; temafloxacin and sparfloxacin were the most active, being fully bactericidal at all three dosage schedules. Additionally, sparfloxacin was found to be fully bactericidal at 15 and 30 mg/kg given five times weekly.

Animals↗
PubMed1992

Vaccination of mice with a soluble protein fraction of Mycobacterium leprae provides consistent and long-term protection against M. leprae infection.

Groups of BALB/c mice were vaccinated intradermally with either Freund's incomplete adjuvant (FIA) alone, 10(7) heat-killed Mycobacterium leprae organisms in FIA, or a number of fractions of M. leprae containing soluble and/or cell wall components. At 1, 3, 6, 9, and 12 months later, vaccinated mice were challenged in the right hind footpad with 5,000 live M. leprae organisms, and vaccine protection was assessed 6 to 8 months later, at the peak of M. leprae multiplication in the negative control (FIA alone), by the two-sample rank-sum test. In these studies, a cell wall fraction rich in peptidoglycan was consistently ineffective. Both heat-killed M. leprae and a fraction containing cell wall and fixed proteins generally protected when the interval between vaccination and challenge was 1 or 3 months but not subsequently. On the other hand, soluble proteins of M. leprae alone or in combination (with cell wall fractions) consistently (14 of 14 instances) afforded highly significant protection (P less than or equal to 0.01) at all challenge intervals up to 1 year after vaccination. These results suggest that the soluble protein fraction of M. leprae offers promise for a vaccine against leprosy.

Animals↗
PubMed1992

Effects of transforming growth factor-beta on murine astrocyte glutamine synthetase activity. Implications in neuronal injury.

Cytokines have been implicated in the pathogenesis of a number of brain diseases in which neurological dysfunction has been attributed to a change in amino acid neurotransmitter metabolism. In the present in vitro study, we investigated the effects of cytokines on astrocyte glutamine synthetase (GS) activity and subsequently on N-methyl-D-aspartate (NMDA) receptor-mediated neurotoxicity. Proinflammatory cytokines IL-1 alpha, IL-1 beta, and IL-6 at a concentration of 20 ng/ml did not affect GS activity; however, tumor necrosis factor-alpha inhibited this activity by 20% in mixed neuronal/astrocyte cultures. Treatment for 24 h with transforming growth factor (TGF)-beta 1 or -beta 2 inhibited up to 60% GS activity. TGF-beta 2 also inhibited GS in enriched astrocyte cultures with an ED50 of 10 pg/ml. Antibodies specific to TGF-beta 2 blocked this effect. Treatment of astrocytes with TGF-beta 2 (250 pg/ml) resulted in markedly dilated rough endoplasmic reticulum. Since astrocyte GS may play a protective role in NMDA receptor-mediated neurotoxicity, we treated mixed neuronal/astrocyte cultures with TGF-beta 2 (250 pg/ml) and found a threefold potentiation of NMDA receptor-mediated neurotoxicity. These data suggest that TGF-beta impairs astrocyte GS function and enhances neurotoxicity, thus providing insight into understanding one mechanism of cytokine-mediated central nervous system disease.

Animals↗
PubMed1992

Morphine potentiates transforming growth factor-beta release from human peripheral blood mononuclear cell cultures.

Opiates modulate a variety of immune responses by peripheral blood mononuclear cells (PBMC). In the present study, we investigated the effect of morphine on the release of several cytokines upon stimulation with mitogens. An interleukin (IL)-4-dependent HT-2 cell proliferation assay was used to quantify transforming growth factor-beta (TGF-beta). IL-6 and tumor necrosis factor-alpha (TNF-alpha) were measured by enzyme-linked immunosorbent assays. Morphine (1 pM and 10 nM) alone did not significantly modulate the release of TGF-beta, IL-6 or TNF-alpha. Upon stimulation with lipopolysaccharide and phytohemagglutinin, PBMC released more (P less than .01) TGF-beta, IL-6 and TNF-alpha than unstimulated PBMC. Exposure of PBMC to morphine (1 pM) for 24 hr substantially amplified (P less than .05) the release of TGF-beta in the following 24 hr incubation period. Morphine did not alter the release of immunodetectable IL-6 or TNF-alpha from stimulated cells. The amplifying effect of morphine on the release of TGF-beta was mediated through a naloxone-sensitive mechanism. Given the fact that TGF-beta has a potent immunosuppressive effect, morphine-potentiated release of TGF-beta from PBMC may be involved in the immunomodulatory activity ascribed to morphine.

Adult↗