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T Zhou

Publications and source records attributed to T Zhou.

At least 145 records · Page 8Linked to original sources
PubMed1996

Hematopoietic cell protein-tyrosine phosphatase-deficient motheaten mice exhibit T cell apoptosis defect.

We previously demonstrated that hematopoietic cell protein-tyrosine phosphatase is one of the molecules that can transduce Fas-mediated apoptosis signals in lymphoid cells. The present study analyzed the effect of defective Fas signaling on the T cell phenotype and apoptosis function in hematopoietic cell protein-tyrosine phosphatase-deficient motheaten mice. Viable motheaten (me(v)/me(v)) mice exhibited increased T cell proliferation and defective activation-induced apoptosis of Fas+ T cells in the lymph node, which was not ascribed to defective Fas ligand function. Furthermore, the Fas-mediated apoptosis defect in activated T cells from me(v)/me(v) mice was confirmed by their resistance to anti-Fas-induced apoptosis. No protein tyrosine dephosphorylation signal was delivered after anti-Fas cross-linking in the lymph node cells of me(v)/me(v) mice as revealed by 32Pi labeling of protein phosphatase substrates. The defective activation-induced apoptosis of Fas+ T cells in me(v)/me(v) mice led to lymphadenopathy with an accumulation of CD4- CD8- B220+ CD3+ T cells. Pneumonitis in me(v)/me(v) mice was associated with infiltration of cycling T cells detected by bromodeoxyuridine uptake in vivo. Thus, T cells from me(v)/me(v) mice are resistant to Fas-mediated apoptosis which results in lymphoproliferative disease and tissue infiltration.

Animals↗
PubMed1996

Greatly accelerated lymphadenopathy and autoimmune disease in lpr mice lacking tumor necrosis factor receptor I.

Fas and TNF receptor I (TNF-RI) share homology at their cytoplasmic death domain and belong to the same gene family, but utilize different pathways to signal activation-induced cell death. To determine the combined effects of defective TNF-RI and Fas signaling on lymphadenopathy and autoimmune disease, we backcrossed TNF-RI knockout mice (Tnfr1(0/0)) with Fas-deficient C57BL/6-lpr/lpr mice. Tnfr1(0/0)lpr/lpr mice developed greatly accelerated lymphadenopathy and autoantibody production compared with C57BL/6-lpr/ lpr mice. Tnfr1(0/0)-lpr/lpr mice also exhibited high mortality and early onset autoimmune disease characterized by massive mononuclear cell infiltration in liver, kidney, lung, and knee joints. These results indicate that the Fas-mediated apoptosis defect in lpr mice is accelerated in the absence of TNF-RI and that normal expression of TNF-RI might partially compensate for the Fas-mediated apoptosis defect of mononuclear cells in lpr mice.

Animals↗
PubMed1996

Inhibition of Nur77/Nurr1 leads to inefficient clonal deletion of self-reactive T cells.

The Nur77/Nurr1 family of DNA binding proteins has been reported to be required for the signal transduction of CD3/T cell receptor (TCR)-mediated apoptosis in T cell hybridomas. To determine the role of this family of DNA-binding proteins in thymic clonal deletion, transgenic (Tg) mice bearing a dominant negative mutation were produced. The transgene consisted of a truncated Nur77 (deltaNur77) gene encoding the DNA-binding domain of Nur77 ligated to a TCR-beta enhancer resulting in early expression in thymocytes. Apoptosis of CD4+CD8+ thymocytes mediated by CD3/TCR signaling was greatly inhibited in the deltaNur77 Tg mice, compared with non-Tg littermates, after treatment with anti-CD3 or anti-TCR antibody in vivo and in vitro. Clonal deletion of self-reactive T cells was investigated in deltaNur77-Db/HY TCR-alpha/beta double Tg mice. There was a five-fold increase in the total number of thymocytes expressing self-reactive Db/HY TCR-alpha/beta in the deltaNur77-TCR-alpha/beta double Tg male mice. Deficient clonal deletion of self-reactive thymocytes was demonstrated by a 10-fold increase in the CD4+CD8+ thymocytes that expressed Tg TCR-alpha/beta. There was an eightfold increase in the CD8+, Db/HY TCR-alpha/beta T cells in the lymph nodes (LN) of delta Nur77-Db/HY TCR-alpha/beta double Tg compared with Db/HY TCR-alpha/beta Tg male mice. In spite of defective clonal deletion, the T cells expressing the Tg TCR were functionally anergic. In vivo analysis revealed increased activation and apoptosis of T cells associated with increased expression of Fas and Fas ligand in LN of deltaNur77-Db/HY TCR-alpha/beta double male mice. These results indicate that inhibition of Nur77/Nurr1 DNA binding in T cells leads to inefficient thymic clonal deletion, but T cell tolerance is maintained by Fas-dependent clonal deletion in LN and spleen.

Animals↗
PubMed1996

The role of programmed cell death as an emerging new concept for the pathogenesis of autoimmune diseases.

Activation-induced apoptosis is a primary mechanism for downmodulation of an immune response leading to immune homeostasis and deletion of T cells with specificities which may be harmful. These include deletion of T cells with self-specificities (autospecific) and excessively high affinity for foreign antigen which may lead to an excessively heightened immune response and septic shock. Surface molecules involved in activation-induced apoptosis involve Fas and Fas ligand (FasL), as well as the T-cell receptor (TCR) which modulates the expression and function of these molecules. Fas signaling mechanisms include the hematopoietic cell phosphatase (HCP) and sphingomyelinase, while TCR-signaling mechanisms include Nur77 and fyn kinase and unknown molecules that modulate expression of FasL. Apoptosis signals are further modulated by inhibitors or inducers of apoptosis including Bcl-2, p53, and interleukin-1 beta converting enzyme (ICE). Further understanding of the interaction of these molecules in autoimmune disease may lead to more specific therapies for immunosuppression tailored to the genetic or environmentally induced, activation-induced apoptosis defect in patients.

Animals↗
PubMed1996

Role of hydrazine in the mechanism of isoniazid hepatotoxicity in rabbits.

Isoniazid (INH) continues to be a highly effective drug in the chemoprophylaxis and treatment of tuberculosis; however, its use is associated with hepatotoxicity (predominantly hepatic necrosis) in 1-2% of individuals. The INH metabolites, acetylhydrazine and hydrazine, have each been implicated as the causative hepatotoxin in INH-induced hepatotoxicity. Using a model of INH-induced hepatotoxicity in rabbits, in which INH-induced hepatotoxicity manifests as hepatic necrosis, hepatic steatosis (hepatic fat accumulation) and hypertriglyceridaemia (elevated plasma triglycerides), we compared the severity of these measures of toxicity with plasma levels of INH, acetylhydrazine and hydrazine. Plasma INH and acetylhydrazine were not correlated with markers of INH-induced hepatic necrosis or fatty changes. Plasma hydrazine at 32 h was correlated significantly with plasma argininosuccinic acid lyase (ASAL, a sensitive marker of hepatic necrosis) activity as area under the curve (r2 = 0.54, P < 0.002) and log plasma ASAL activity at 48 h after the first dose of INH (r2 = 0.53, p < 0.005), but not with fatty changes. These results show in this model of INH-induced hepatotoxicity in rabbits that hydrazine, and not INH or acetylhydrazine, is most likely involved in the pathogenic mechanism of hepatic necrosis.

Animals↗
PubMed1996

Role of calmodulin in HIV-potentiated Fas-mediated apoptosis.

The recently demonstrated extraordinary rate of turnover of T cells in human immunodeficiency virus (HIV)-1-infected patients and the apparently concomitant high rate of viral production and death are consistent with a large amount of cell death directly due to infection. Apoptosis may be one of the major forms of T cell death in HIV-1 infection. Many apoptotic pathways depend on calcium and therefore would be expected to involve calmodulin. As the HIV-1 envelope glycoprotein, gp160, contains two known calmodulin-binding domains, we investigated the possibility that the cytoplasmic domain of the HIV-1 envelope protein gp160 could enhance Fas-mediated apoptosis, the major form of apoptosis in lymphocytes. Our studies have shown that 1) transfection of H9 and MOLT-4 cells with a non-infectious HIV proviral clone, pFN, which expresses wild-type gp160, leads to enhanced Fas-mediated apoptosis, 2) transfection of MOLT-4 cells with a pFN construct pFN delta 147, which expresses a carboxyl-terminally truncated gp160 lacking the calmodulin-binding domains, produces less Fas-mediated apoptosis than transfection with pFN, and 3) the calmodulin antagonists trifluoperazine and tamoxifen completely inhibit the pFN enhancement of Fas-mediated apoptosis in MOLT-4 cells. We have replicated all of these results using the vectors pSRHS and pSRHS delta 147, which express wild-type gp160 and truncated gp160, respectively, in the absence of other viral proteins. These investigations provide a mechanism by which HIV-1 may induce apoptosis and a possible intracellular target for future therapeutics.

Amino Acid Sequence↗
PubMed1996

Autoimmune disease results from multiple interactive defects in apoptosis induction molecules and signaling pathways.

Activation induced cell death (AICD) plays a critical role in eliminating autoimmune cells and limiting inflammation after activation. The two major signaling molecules for AICD are the Fas and TNF-R pathways of apoptosis. Defective Fas apoptosis in lpr/lpr mice results in a compensatory increase in TNF-R/TNF-mediated apoptosis. TNF/TNF-R has been shown to be a compensatory pathway of apoptosis in T cells and macrophages of lpr/lpr mice. Therefore, early production of TNF/TNF-R limit an immune response by inducing AICD in the absence of an intact Fas/Fas ligand apoptosis pathway. However, increased TNF production in lpr mice also lead to increased susceptibility to septic shock and autoimmune disease such as arthritis. Therefore TNF production during an inflammatory response can downmodulate this response, but this also results in the failure to downmodulate TNF production leading to septic shock and arthritis. A second pathway of AICD is mediated by Nur77 after T cell stimulation through the CD3 molecule. Mice with defective Nur77 signaling undergo AICD using the Fas-Fas ligand pathway to eliminate autoreactive T cells. A third defect of AICD is observed in HCP-mutant me/me (motheaten) mice which develop autoimmune disease related to defective Fas apoptosis signaling. Therefore, multiple interactive pathways play a role in limiting development of autoimmunity.

Animals↗
PubMed1995

Increased susceptibility of fas mutant MRL-lpr/lpr mice to staphylococcal enterotoxin B-induced septic shock.

MRL-lpr/lpr mice are defective in the fas Ag/APO-1 apoptosis gene (CD95). Using the hepatotoxin D-galactosamine (D-GalNH2), we demonstrate that MRL-lpr/lpr mice have an increased susceptibility to staphylococcal enterotoxin B (SEB)-induced lethal shock, which causes them to exhibit the septic shock-like behaviors of fur ruffling and listlessness, and death occurs within 8 to 18 h. SEB susceptibility is greater in V beta 8.2 TCR transgenic MRL-lpr/lpr mice than in nontransgenic mice. In studies designed to elucidate the molecular pathways of SEB-induced septic shock, we found that C57Bl/6.Ab0/Ab0, MHC class II-deficient "C2D" mice, but not C57Bl/6-(+/+) mice, are nonresponsive to challenge with SEB. C2D mice, backcrossed with the fas mutation resulting in double-knockout C2D;lpr/lpr mice, are more susceptible to challenge with SEB/D-GalNH2. The LD50s for C57Bl/6.C3H-gld/gld "fas ligand-mutant mice" challenged with SEB/D-GalNH2 were comparable to C57Bl/6.MRL-lpr/lpr and MRL-lpr/lpr mice, suggesting that reciprocal mutations in either fas or fas ligand increases susceptibility to bacterial superantigens (SAGs). SEB-induced lethal shock can be reversed by treatment with Abs to V beta 8 TCR, MHC class II Ia+, IL-2, and TNF-alpha, by the immunosuppressant cyclosporin A, or by treatment with carbocyclic nucleoside analogues. These data indicate that SAG-induced septic shock is dependent on interactions with the TCR and MHC class II Ags, and they also suggest a critical role for a functional fas and/or fas ligand in resistance to SAG-induced septic shock.

Animals↗
PubMed1995

Interaction of substrate and effector binding sites in the ArsA ATPase.

The ars operon of plasmid R773 confers resistance to antimonials and arsenicals in Escherichia coli by encoding an ATP-dependent extrusion system for the oxyanions. The catalytic subunit, the ArsA protein, is an ATPase with two nucleotide binding consensus sequences, one in the N-terminal half and one in the C-terminal half of the protein. The ArsA ATPase is allosterically activated by tricoordinate binding of As(3+) or Sb(3+) to three cysteine thiolates. Previous measurements suggested that the intrinsic fluorescence of tryptophans might be useful for examining binding of Mg2+ ATP and antimonite. In the present study an increase in intrinsic tryptophan fluorescence was observed upon addition of Mg2+ ATP. This enhancement was reversed by addition of antimonite. The ArsA protein contains four tryptophan residues: Trp159, Trp253, Trp522, and Trp524. The first two were altered to tyrosine residues by site-directed mutagenesis. Cells expressing both the arsAW159Y and arsAW253Y mutations retained resistance to arsenite, and the purified W159Y and W253Y proteins retained ATPase activity. While the intrinsic tryptophan fluorescence of the W253Y protein responded to addition of Mg2+ ATP, intrinsic tryptophan fluorescence in the purified W159Y protein was no longer enhanced by substrate. These results suggest that Trp159 is conformationally coupled to one or both of the nucleotide binding sites and provides a useful probe for the interaction of effector and substrate binding sites.

Adenosine Triphosphatases↗
PubMed1995

Prevention of age-related T cell apoptosis defect in CD2-fas-transgenic mice.

T cell dysfunction and thymic involution are major immunologic abnormalities associated with aging. Fas (CD95) is a bifunctional molecule that is critical for apoptosis and stimulation during T cell development, but the role of Fas during aging has not been determined. Fas expression and function on T cells from old (22-26-mo-old) mice was compared with young (2-mo-old) mice and old CD2-fas-transgenic mice. Fas expression and ligand-induced apoptosis were decreased on T cells from old mice compared with young mice. This correlated with an age-related increase in CD44+Fas- T cells. There was a marked decrease in the proliferation of T cells from old mice after anti-CD3 stimulation compared with young mice. Anti-CD3-stimulated T cells from young mice exhibited increased production of interleukin (IL)-2 and decreased production of interferon-gamma and IL-10 compared with old mice. There was an age-related decrease in the total thymocyte count from 127 +/- 10 cells in young mice compared with 26 +/- 8 x 10(6) in old mice. In 26-mo-old CD2-fas-transgenic mice, Fas and CD44 expression, Fas-induced apoptosis, T cell proliferation, and cytokine production were comparable to that of the young mice. These results suggest that T cell senescence with age is associated with defective apoptosis, and that the CD2-fas transgene allows maintenance of Fas apoptosis function and T cell function in aged mice comparable to that of young mice.

Aging↗
PubMed1995

Susceptibility to hepatocellular carcinoma is associated with genetic variation in the enzymatic detoxification of aflatoxin B1.

Aflatoxin B1 (AFB1) has been postulated to be a hepatocarcinogen in humans, possibly by causing p53 mutations at codon 249. AFB1 is metabolized via the phase I and II detoxification pathways; hence, genetic variation at those loci may predict susceptibility to the effects of AFB1. To test this hypothesis, genetic variation in two AFB1 detoxification genes, epoxide hydrolase (EPHX) and glutathione S-transferase M1 (GSTM1), was contrasted with the presence of serum AFB1-albumin adducts, the presence of hepatocellular carcinoma (HCC), and with p53 codon 249 mutations. Mutant alleles at both loci were significantly overrepresented in individuals with serum AFB1-albumin adducts in a cross-sectional study. Mutant alleles of EPHX were significantly overrepresented in persons with HCC, also in a case-control study. The relationship of EPHX to HCC varied by hepatitis B surface antigen status and indicated that a synergistic effect may exist. p53 codon 249 mutations were observed only among HCC patients with one or both high-risk genotypes. These results indicate that individuals with mutant genotypes at EPHX and GSTM1 may be at greater risk of developing AFB1 adducts, p53 mutations, and HCC when exposed to AFB1. Hepatitis B carriers with the high-risk genotypes may be an even greater risk than carriers with low-risk genotypes. These findings support the existence of genetic susceptibility in humans to the environmental carcinogen AFB1 and indicate that there is a synergistic increase in risk of HCC with the combination of hepatitis B virus infection and susceptible genotype.

Aflatoxin B1↗
PubMed1995

Autoimmunity, apoptosis defects and retroviruses.

Autoimmunity and AIDS both share the common feature of increased expression of retroviral protein products and abnormal apoptosis of immune cells (81). This leads to a more global immunomodulatory defect (82-84). The challenge in the future will be to devise compounds that can either regulate the effect of the retroviral products on apoptosis, or that can inhibit apoptosis pathways in order to restore normal immune system function.

Amino Acid Sequence↗
PubMed1995

A model of isoniazid-induced hepatotoxicity in rabbits.

Isoniazid (INH) continues to be an effective drug used for chemoprophylaxis and treatment of tuberculosis. Unfortunately, INH is associated with significant hepatotoxicity in up to 2% of individuals exposed, and if this adverse event is not recognized early it can be fatal. Research on INH-induced hepatotoxicity has been hampered by the lack of a suitable animal model that closely resembles the toxicity in humans. The mechanism of INH-induced hepatotoxicity is still unknown. The present study describes the development of a reliable model of INH-induced hepatotoxicity in rabbits. The protocol involves repeated injections of INH over a 2-day period, resulting in significant hepatic necrosis as indicated by elevations of plasma argininosuccinic acid lyase activity. Pretreatment with phenobarbital increased the occurrence of INH-induced hepatic necrosis from approximately 60% (9 out of 15 rabbits) with INH alone to more than 90% (13 out of 14 rabbits). Morphological indices were used to demonstrate the presence of INH-induced hepatotoxicity, and biochemical indices were used to demonstrate both the presence and severity of INH-induced hepatotoxicity in this model. This model may prove useful for further investigations into the mechanism of INH-induced hepatotoxicity.

Administration, Oral↗