Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

STATs play key roles in immune function. We examined the role of STAT5a/b in allograft rejection. STAT5a/b-deficient mice showed a 4-fold increased survival time of heart allografts (p < 0.01). Unlike wild type, purified STAT5a/b-/- T cells transferred to Rag1-/- recipients failed to mediate heart allograft rejection until supplemented with STAT5a/b-/- B cells. In vitro, STAT5a/b-/- T cells did not proliferate in response to Con A or alloantigens but entered apoptosis within 48 h (95%). Activated STAT5a/b-/- T cells showed increased expression of proapoptotic (caspases, DNA repair genes, TNF/TNFR-associated factor family genes) and decreased antiapoptotic mRNAs in microarrays, while Western blots confirmed reduced antiapoptotic Bcl-2 and elevated proapoptotic Bax protein expression. Interestingly, at 24 h postactivation, STAT5a/b+/+ and STAT5a/b-/- T cells produced similar levels of IL-2, IL-4, IL-10, and IFN-gamma mRNA; ELISPOT assay showed an equivalent number of IL-4- and IFN-gamma-producing T cells in both STAT5a/b+/+ and STAT5a/b-/- splenic populations. Sera from STAT5a/b+/+ and STAT5a/b-/- rejectors had donor-specific IgM, IgG1, IgG2a, and IgG2b Ab, while STAT5a/b deficiency had no impact on B cell survival or proliferation in response to LPS. Compared with allografts from STAT5a/b+/+ recipients, heart allografts from STAT5a/b-/- recipients had markedly reduced infiltration by CD4 and CD8 T cells but increased infiltration by B cells and dense endothelial deposition of C4d, a marker of humoral rejection. Thus, activated STAT5a/b-/- T cells produce cytokines prior to entering apoptosis, thereby promoting differentiation of B cells yielding donor-specific IgM and IgG Ab that mediate allograft rejection.
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PMID:Allograft rejection requires STAT5a/b-regulated antiapoptotic activity in T cells but not B cells. 1636 3

P-selectin glycoprotein ligand-1 (PSGL-1) mediates the initial tethering of leukocytes to activated platelets and endothelium. We report molecular cloning and characterization of the rat PSGL-1 gene. A neutralizing Ab was generated, and its binding epitope was mapped to the N-terminal binding region of rat PSGL-1. We examined the effects of early PSGL-1 blockade in rat liver models of cold ischemia, followed by ex vivo reperfusion or transplantation (orthotopic liver transplantation (OLT)) using an anti-PSGL-1 Ab with diminished Fc-mediated effector function. In the ex vivo hepatic cold ischemia and reperfusion model, pretreatment with anti-PSGL-1 Ab improved portal venous flow, increased bile production, and decreased hepatocellular damage. Rat pretreatment with anti-PSGL-1 Ab prevented hepatic insult in a model of cold ischemia, followed by OLT, as assessed by 1) decreased hepatocellular damage (serum glutamic oxaloacetic transaminase/glutamic-pyruvic transaminase levels), and ameliorated histological features of ischemia/reperfusion injury, consistent with extended OLT survival; 2) reduced intrahepatic leukocyte infiltration, as evidenced by decreased expression of P-selectin, ED-1, CD3, and OX-62 cells; 3) inhibited expression of proinflammatory cytokine genes (TNF-alpha, IL-1beta, IL-6, IFN-gamma, and IL-2); and 4) prevented hepatic apoptosis accompanied by up-regulation of antiapoptotic Bcl-2/Bcl-xL protective genes. Thus, targeting PSGL-1 with a blocking Ab that has diminished Fc-mediated effector function is a simple and effective strategy that provides the rationale for novel therapeutic approaches to maximize the organ donor pool through the safer use of liver transplants despite prolonged periods of cold ischemia.
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PMID:Molecular characterization of rat leukocyte P-selectin glycoprotein ligand-1 and effect of its blockade: protection from ischemia-reperfusion injury in liver transplantation. 1636 57

The airway epithelium functions primarily as a barrier to foreign particles and as a modulator of inflammation. Apoptosis is induced in airway epithelial cells (AECs) by viral and bacterial infections, destruction of the cytoskeleton, or by exposure to toxins such as high oxygen and polycyclic hydrocarbons. Various growth factors and cytokines including TGF-beta, IFN-gamma, or the activators of the death receptors, TNF-alpha and FasL, also induce apoptosis in AECs. However, cell death is observed in maximally 15% of AECs after 24 h of treatment. Preincubation with IFN-gamma or a zinc deficiency increases the percentage of apoptotic AECs in response to TNF-alpha or FasL, suggesting that AECs have mechanisms to protect them from cell death. Apoptosis of AECs is a major mechanism in reducing cell numbers after hyperplastic changes in airway epithelia that may arise due to major injuries in response to LPS or allergen exposures. Resolution of hyperplastic changes or changes during prolonged exposure to an allergen is primarily regulated by the Bcl-2 family of proteins. Fas and FasL are both expressed in AECs, and their main function may be to control inflammation by inducing Fas-induced death in inflammatory cells without inducing apoptosis in neighboring cells. Furthermore, AECs engulf dying eosinophils to clear them by phagocytosis. Therefore, in the airway epithelium apoptosis serves three main roles: (1) to eliminate damaged cells; (2) to restore homeostasis following hyperplastic changes; and (3) to control inflammation, and thereby support the barrier and anti-inflammatory functions.
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PMID:Roles of apoptosis in airway epithelia. 1643 4

Naive, CD4+ T cells proliferate extensively but fail to differentiate when they are transferred into unirradiated recipients that express alloantigen or transgenic antigen on all MHC class II+ cells. Addition of an agonist antibody to OX40 (CD134), a costimulatory TNF receptor family member expressed on activated CD4+ T cells, enables the proliferating T cells to accumulate as differentiated effector cells and kill the host animals. The donor T cells from anti-OX40-treated animals express high levels of IL-2R alpha (CD25) and acquire the ability to secrete IFN-gamma when stimulated with IL-12 and IL-18. OX40 promotes differentiation by 48 h in T cell priming, before changes in Bcl-2 expression or cell recovery become apparent. We found that a Bcl-2 transgene or deficiency in Fas or TNFR1 failed to influence accumulation of differentiated donor cells, and found larger changes in expression of cytokine and cytokine receptor genes than in survival genes. Accumulation of differentiated CD4+ effector T cells is initiated directly through OX40, but some OX40-deficient donor cells can gain effector function as bystanders to OX40+/+ cells. Taken together, these data suggest that CD4+ T cell differentiation to effector function is an important effect of OX40 engagement under conditions of ubiquitous antigen presentation.
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PMID:OX40 (CD134) engagement drives differentiation of CD4+ T cells to effector cells. 1654 71

Bcl-2 family proteins play a crucial role in the regulation of the mitochondrial pathway that leads to apoptosis. Members of the Bcl-2 family can be divided into the anti-apoptotic proteins such as Bcl-2 and Bcl-X(L), and the pro-apoptotic proteins such as Bax and Bak and the BH3-only proteins. In this study, siRNA constructs to silence the Bax and Bak genes in Chinese hamster ovary (CHO) cells were generated. Stable CHO cell lines in which the expression of Bax and Bak were significantly knocked down were screened by Western blot analysis and confirmed by RT-PCR. CHO cells with both Bax and Bak knocked down showed a clear resistance against cytotoxic lectins and UV irradiation-induced apoptosis. Compared to original CHO-K1 cells, these cells also survived longer when cultured under extreme conditions such as complete nutrient depletion or in high-osmolality medium. CHO cells with both Bax and Bak genes knocked down displayed an extended lifespan as well as higher viable cell densities in fed-batch cultures, both in adherent form on microcarrier beads and in suspension. The IFN-gamma productivity by a rCHO IFN-gamma cell line in which both Bak and Bax were knocked down increased by 35% compared to the control cells. These results indicate that the genetic inactivation of Bax and Bak in recombinant CHO cells can be an effective strategy in delaying the onset of apoptosis in batch and fed-batch cultures.
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PMID:RNAi suppression of Bax and Bak enhances viability in fed-batch cultures of CHO cells. 1686 May 84

It is NO that mediates the inhibitory effect of IFN-gamma, MIP-1alpha and TNFalpha on hematopoiesis. However, the mechanism for NO effect on the hematopoietic system is likely to not clear. In the current work, we demonstrates that NO can directly suppress the colony formation of granulocyte/macrophage in vitro. Using a granulocyte/macrophage progenitor (GMP) model, HL-60 cell line, we show that NO inhibits the proliferation of HL-60 cells by inducing G0/G1 arrest and apoptosis in a dose- and time-dependent manner. Exposure of HL-60 cells to 1mM SNP for 2-48h results in marked decrease in Akt activation and Bad phosphorylation. Constitutively active Akt overexpression reduces NO-induced apoptosis and cell cycle arrest in HL-60 cells. A further investigation on apoptosis related protein shows that NO induces Bid cleavage and Bax expression but down-regulates the expression of Bcl-2 and Bcl-xL. We also demonstrate here that G0/G1 arrest is resulted from NO-induced disruption of cell cycle balance, which is mediated by up-regulation of p21(waf/cip1), p27(kip1) and down-regulation of cyclin D1, cyclin E. In brief, NO-induced apoptosis and G0/G1 arrest is mediated through regulation of apoptosis and cell cycle related protein, which may depend on Akt deactivation by NO, ultimately led to its inhibitory effect on hematopoiesis.
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PMID:Nitric oxide induces promyelocytic cell growth arrest and apoptosis through deactivation of Akt pathway. 1695 May 11

We have investigated the relationship between gene expression of Bcl 2 and Bax and the therapeutic effect in oral cancer patients. A significant correlation between Bcl-2/Bax gene expression ratio in the peripheral blood mononuclear cells (PBMCs) from the patients, and the therapeutic effect of radiation therapy in combination with UFT and OK-432, as well as survival rate, was observed. In addition, the statistically significant correlation was also observed between Bcl-2/Bax ratio and IFN-gamma and NK activity induced with OK-432. These findings suggest that Bcl-2 and Bax gene expression in PBMCs may be useful as a prognostic factor in oral cancer patients.
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PMID:[The relationship between gene expression of Bcl-2 and Bax and the therapeutic effect in oral cancer patients]. 1721 87

Epulus is a benign gingival tumour of unknown aetiopathogenesis. Classification is inconsistent, and standard management strategies are lacking. Epuli are generally believed to be inflammatory rather than neoplastic lesions. The literature does not present any molecular analysis of the tumour characteristics. The purpose of the present study was to compare benign (epulus) and malignant (cancer) gingival hyperplasias with regard to the activity of the genes of apoptosis, proliferation, and inflammation using RT-PCR. The investigation involved 70 patients with epuli and 15 patients with gingival squamous cell carcinoma. Each subject had specimens collected from the tumour, tissue margin (incision line), and healthy tissue. Molecular investigations by RT-PCR were used to evaluate expression levels of the genes associated with apoptosis (Bcl-2, Bax, Bcl-2/Bax), proliferation (H3 histone), and inflammatory processes (IFN-gamma, IFNgamma-R1, IFN-gammaR2, IFN-gammaR1/IFN-gammaR2). Correlations have been disclosed between apoptosis and proliferation genes expression in giant cell epuli and high-differentiated gingival squamous cell carcinoma. In RT-PCR molecular analysis, giant cell epulus shows characteristics of a neoplastic lesion, while other epulus types seem to be inflammatory tumours.
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PMID:Differential diagnosis of gingival hyperplasia based on IFN-gamma-stimulated gene expression using RT-PCR. 1732 39

The formation of immunological memory is a hallmark of adaptive immunity and the goal of vaccination. For CD8(+ )T cells, successful generation of memory cells has been linked to IL-7 receptor alpha (IL-7Ralpha) expression, suggesting a role for IL-7 signaling, which in turn is important for preventing T cell apoptosis. We thus investigated the kinetics and changes of IL-7Ralpha and anti-apoptotic protein Bcl-2 expression levels in tetanus toxoid (TT)-specific CD4(+ )T cells at different time points prior and after TT re-immunization of TT-immune individuals. Prior to re-immunization, most TT-specific CD4(+ )T cells were high IL-2 producers, CD45RA(-)CCR7(+), IL-7Ralpha(high)Bcl-2(high) cells, resembling typical long-lived central memory cells. Already 5 days, and more importantly at the peak of the response, after TT re-immunization, a substantial fraction of these cells secreted also IFN-gamma, down-regulated CCR7, IL-7Ralpha and Bcl-2 and became Ki67 positive, resembling effector memory cells. In contrast, TT-specific CD4(+ )T cells found 60 days or later after re-immunization were again as baseline. Interestingly, a significant fraction of IL-7Ralpha(high)Bcl-2(high) TT-specific CD4(+ )T cells, i.e. the proposed memory cell precursors, remained stable at any time point upon re-immunization. Together, these results suggest that IL-7Ralpha expression levels might be a useful marker for identifying long-lived Ag-specific CD4(+ )T cells in memory T cells.
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PMID:Functional and phenotypic characterization of tetanus toxoid-specific human CD4+ T cells following re-immunization. 1737 91

Bacterial cytolethal distending toxins (CDTs) containing DNase I-like activity can induce limited host DNA damage that leads to activation of the DNA-damage repair responses in cultured cell lines. However, in vivo experimental evidence linking CDTs to carcinogenesis is lacking. In this study, infection of A/JCr mice with an isogenic mutant of Helicobacter hepaticus lacking CDT activity (CDT mutant) induced chronic hepatitis comparable to wild-type H. hepaticus (Hh) infection at both 4 and 10 months post inoculation (MPI); however, the CDT mutant-infected mice did not develop hepatic dysplasic nodules at 10 MPI, whereas those infected with Hh did. There was no significant difference in hepatic colonization levels between the CDT mutant and Hh at both time points (P > 0.05). At 4 MPI, mice infected with Hh had significantly enhanced hepatic transcription of proinflammatory TNF-alpha, IFN-gamma and Cox-2, growth mediators IL-6 and TGF-alpha, anti-apoptotic Bcl-2 and Bcl-X(L), and increased hepatocyte proliferation (P < 0.05) compared with the control or the CDT mutant-infected mice. In addition, Hh infected male mice had upregulated hepatic mRNA levels of RelA (p65), p50, GADD45beta and c-IAP1, components of the NF-kappaB pathway compared with the CDT mutant-infected mice. At 10 MPI, Hh infection was associated with significant upregulation of IL-6 mRNA. Activation of the inflammatory NF-kappaB pathway and upregulation of proinflammatory cytokines plus IL-6 in the Hh but not in the CDT mutant-infected mice suggest that Hh CDT plays a key role in promoting the dysplastic changes in Hh-infected mouse livers.
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PMID:Bacterial cytolethal distending toxin promotes the development of dysplasia in a model of microbially induced hepatocarcinogenesis. 1744 86


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