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ABSTRACT: Previously we reported that TGF-β1-induced growth suppression was associated with a decrease in mutant p53 levels in B-cell lymphoma cells. The goal of the present study was to understand the mechanism involved in TGF-β1-mediated down-regulation of mutant p53. In RL and CA46, two B-cell lymphoma cell lines, TGF-β1 treatment caused down-regulation of E2F-1 transcription factor resulting in the down-regulation of both p14(ARF) and mutant p53, leading to growth arrest. Experimental overexpression of E2F-1 increased p14(ARF) level and blocked TGF-β1-induced down-regulation of p14(ARF). Overexpression of p14(ARF) blocked the down-regulation of mutant p53 and prevented growth arrest. p14(ARF) also attenuated TGF-β1-induced p21(Cip1/WAF1) induction, which was reversible by p53 siRNA, indicating the involvement of mutant p53 in controlling the TGF-β1-induced expression of p21(Cip1/WAF1). The interaction observed between phospho-Smad2 and mutant p53 in the nucleus could be the mechanism responsible for blocking the growth-suppressive effects of TGF-β1. In RL cells, p14(ARF) is present in a trimer consisting of mutant p53-Mdm2-p14(ARF) and in a dimer consisting of Mdm2-p14(ARF). Because it is known that Mdm2 can degrade p53, it is possible that, in its trimeric form, p14(ARF) is able to stabilize mutant p53 by inhibiting Mdm2. In its dimeric form, p14(ARF) may be sequestering Mdm2, limiting its ability to degrade p53. Collectively, these data demonstrate a unique mechanism in which the inhibition of TGF-β1-mediated growth suppression by mutant p53 can be reversed by the down-regulation of its stabilizing protein p14(ARF). This work suggests that the high levels of p14(ARF) often found in tumor cells could be a potential therapeutic target.
Journal of Biological Chemistry 05/2012; 287(27):23184-95. · 4.77 Impact Factor
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ABSTRACT: CXCL12 is a pleiotropic chemokine involved in multiple different processes such as immune regulation, inflammatory responses, and cancer development. CXCL12 is also a potent chemokine involved in chemoattraction of T cells to the site of infection or inflammation. Mammalian target of rapamycin (mTOR) is a serine-threonine kinase that modulates different cellular processes, such as metabolism, nutrient sensing, protein translation, and cell growth. The role of mTOR in CXCL12-mediated resting T cell migration has yet to be elucidated.
Rapamycin, an inhibitor of mTOR, significantly inhibits CXCL12 mediated migration of both primary human resting T cells and human T cell leukemia cell line CEM. p70(S6K1), an effector molecule of mTOR signaling pathway, was knocked down by shRNA in CEM cells using a lentiviral gene transfer system. Using p70(S6K1) knock down cells, we demonstrate the role of mTOR signaling in T cell migration both in vitro and in vivo.
Our data demonstrate a new role for mTOR in CXCL12-induced T cell migration, and enrich the current knowledge regarding the clinical use of rapamycin.
PLoS ONE 01/2011; 6(9):e24667. · 4.09 Impact Factor
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ABSTRACT: The role of T cells in innate immunity is not well defined. In this report, we show that a subset of human peripheral blood CD4(+) T cells responds to IL-12 plus IL-18, but not to IL-12 or IL-18 alone, by producing IFN-γ in the absence of any antigenic stimulation or cell proliferation. Intracellular staining reveals a small percentage of resting CD4(+) T cells (0.5 to 1.5%) capable of producing IFN-γ in response to IL-12 plus IL-18. Interestingly, both naïve (CD45RA(+)) and memory (CD45RO(+)) CD4(+) populations were responsive to IL-12 plus IL-18 stimulation in producing IFN-γ. The expression of IFN-γinduced by IL-12 and IL-18 is sensitive to rapamycin and SB203580, indicating the possible involvement of mTOR and p38 MAP kinase, respectively, in this synergistic pathway. While p38MAP kinase is involved in transcription, mTOR is involved in message stabilization. We have also shown that NFκB family member, cRel, but not GADD45β and GADD45γ, plays an important role in IL-12 plus IL-18-induced IFN-γ transcription. Thus, the present study suggests that naïve CD4(+) T cells may participate in innate immunity or amplify adaptive immune responses through cytokine-induced antigen-independent cytokine production.
PLoS ONE 01/2011; 6(5):e18553. · 4.09 Impact Factor
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ABSTRACT: There are multiple mechanisms by which cells evade TGF-β-mediated growth inhibitory effects. In this report, we describe a novel mechanism by which cells become resistant to TGF-β-mediated growth suppression. Although having all the components of the TGF-β signaling pathway, different cell lines, RL, HaCaT, and BJAB, have different sensitivities toward TGF-β-induced growth suppression. The TGF-β resistance of RL, a B-cell lymphoma cell line, was due to ligand-induced downregulation of TGF-β receptor II (TβRII) and only transient TGF-β induced nuclear translocation of Smad2 and Smad3. With low-dose phorbol 12-myristate 13-acetate (PMA) or anti-IgM treatment, TGF-β sensitivity was restored by stabilizing TβRII expression and sustaining TGF-β signaling. The MEK inhibitor, U0126, blocked both PMA- and anti-IgM-induced upregulation of TβRII. In HaCaT and BJAB, two TGF-β-sensitive cell lines, which had higher basal levels of phospho-MEK and TβRII compared with RL, U0126 induced downregulation of TβRII and blocked subsequent TGF-β signaling. Similar results were also obtained with normal B cells, where MEK1 inhibitor downregulated TβRII and subsequent TGF-β signaling. Constitutively active MEK1, but not constitutively active ERK2, induced upregulation of TβRII. Furthermore, TβRII physically interacted with the constitutively active MEK1, but not with wild-type MEK1, indicating involvement of active MEK1 in stabilizing TβRII. Collectively, our data suggest a novel mechanism for MEK1 in regulating the sensitivity to TGF-β signaling by stabilizing TβRII.
Molecular Cancer Research 01/2011; 9(1):78-89. · 4.29 Impact Factor
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ABSTRACT: Tumor necrosis factor (TNF) induces expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) but lymphotoxin β (LTβ) does not. Here we report that priming of cells with agonistic LTβ receptor antibody synergistically enhanced TNF-induced GM-CSF expression. The LTβ priming process was not due to an increase in TNF-mediated nuclear translocation of p65, p65 DNA binding, or NF-κB transactivational activity. The synergistic effect of LTβ priming was not observed with other TNF-responsive genes such as Ccl2 or RelB, which suggested that this effect was not a general increase in TNF signaling. Furthermore, RelB and p65 were both independently recruited to the GM-CSF promoter when cells were primed with LTβ followed by TNF treatment. As a consequence, an increase in both chromatin accessibility and the recruitment of RNA polymerase II were observed to the GM-CSF promoter. Taken together, these findings suggested that LTβ signaling amplified TNF-mediated GM-CSF expression by facilitating chromatin access and the co-recruitment of RNA polymerase II to increase gene transcription. Moreover, the novel priming process described here underscores the complexity of the interactions between the classical and alternative NF-κB signaling pathways.
Journal of Biological Chemistry 11/2010; 286(2):1093-102. · 4.77 Impact Factor
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ABSTRACT: Activation-induced deaminase (AID) is expressed in activated B lymphocytes and initiates somatic hypermutation and class switch recombination. To determine if different stimuli affect the expression and function of AID, we monitored AID activity in murine B cells stimulated ex vivo with various ligands. AID was rapidly expressed at both the RNA and protein levels following stimulation with LPS, LPS plus IL-4, and anti-CD40 plus IL-4, but was delayed after stimulation with anti-IgM plus IL-4. By day 4, AID was expressed in all groups; however, cells stimulated with anti-IgM plus IL-4 did not undergo switch recombination. These cells expressed normal levels of gamma 1 germline transcripts, implying that the gamma 1 switch region was accessible. Furthermore, switching was suppressed by the addition of anti-IgM to cells stimulated with LPS plus IL-4 or anti-CD40 plus IL-4, even though AID was expressed. The lack of class switch recombination could be reversed by inhibition of phosphatidylinositol 3-kinase (PI3K). This suggests that activation through the B cell receptor induces PI3K, which interferes with the function of AID.
Molecular Immunology 04/2008; 45(6):1799-806. · 2.90 Impact Factor
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ABSTRACT: Abnormal nuclear factor-kappaB (NF-kappaB) signaling has been attributed to the initiation and progression of cancer. Posttranslational modification of p65 facilitates optimal NF-kappaB signaling after activation. Here, we show that the phosphorylation of serine 536 was required for p65-mediated transcription and I kappa B alpha expression in fibroblasts. Furthermore, tumor necrosis factor (TNF) treatment slightly induced p65 phosphorylation, and both unphosphorylated and phosphorylated p65 translocated into the nucleus. The phosphorylation of serine 536 was not required for p65-mediated protection from TNF cytotoxicity and Traf1 induction in fibroblasts. Also, the corecruitment of p65 and RNA polymerase II to the Traf1 enhancer region did not require p65 phosphorylation. However, the corecruitment of p65 and RNA polymerase II to the Csf2 promoter required the phosphorylation of serine 536. These findings suggested that the requirement of serine phosphorylation at residue 536 and the distance between the NF-kappaB response element and the start of transcription may influence which genes will be transcribed.
Cancer Research 01/2008; 67(23):11218-25. · 7.86 Impact Factor
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ABSTRACT: Resistance to transforming growth factor (TGF)-beta1-mediated growth suppression in tumor cells is often associated with the functional loss of TGF-beta receptors. Here we describe two B-cell lymphoma cell lines (DB and RL) that differ in their sensitivity to TGF-beta1-mediated growth suppression. The TGF-beta1-resistant cell line DB lacked functional TGF-beta receptor II (T beta RII) in contrast to the TGF-beta-responsive cell line RL, whereas both cell lines had comparable levels of receptor I (T beta RI). Lack of functional T beta RII was correlated with the lack of TGF-beta1-induced nuclear translocation of phospho-Smad3 and phospho-Smad2, the lack of nuclear expression of p21(Cip1/WAF1), and the down-regulation of c-Myc in DB cells. Transfection of wild-type, but not a C-terminal-truncated, form of T beta RII rendered the DB cell line responsive to TGF-beta1-mediated growth suppression. Analysis of the T beta RII gene in DB cells revealed the absence of T beta RII message, which was reversed upon 5'-azacytidine treatment, indicating that the promoter methylation might be the cause of gene silencing. Promoter analysis revealed CpG methylations at -25 and -140 that correlated with the gene silencing. These data suggest that promoter methylation plays an important role in T beta RII gene silencing and subsequent development of a TGF-beta1-resistant phenotype by some B-cell lymphoma cells.
Blood 07/2007; 109(12):5301-7. · 9.90 Impact Factor
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ABSTRACT: The association of the NF-kappaB p65/p50 dimer with IkappaBalpha plays a pivotal role in regulating its nuclear translocation and gene transcription. In addition, serine phosphorylation at various sites of the p65 subunit has been shown to be important in initiating transcription. Here we demonstrate that the regulation of nuclear translocation of p65 phosphorylated at serine 536 is not dependent on IkappaBalpha. Stimulation of either Jurkat or normal human T cells resulted in the nuclear translocation of phospho-p65 (Ser(536)). In addition, the phospho-p65 (Ser(536)) was not associated with either IkappaBalpha or p50, and the nuclear translocation of phospho-p65 (Ser(536)), but not total p65, was unaffected by the proteosome inhibitor MG-132, which blocks IkappaB protein degradation and prevents p65/p50 dimer nuclear translocation. Accordingly, the co-expression of a dominant negative mutant of IkappaBalpha blocked the transcriptional activity mediated by wild type but not the dominant positive p65 mutant (S536D). Furthermore, the transfection of the S536D form of p65 led to the induction of interleukin-8 transcription following stimulation, whereas the S536A form, which cannot be phosphorylated at this site, did not. Together, the findings suggest that p65 phosphorylated on serine 536 is not associated with or regulated by IkappaBalpha, that it has a distinct set of target genes, and that it may represent a noncanonical NF-kappaB pathway that is independent of IkappaBalpha regulation.
Journal of Biological Chemistry 11/2005; 280(41):34538-47. · 4.77 Impact Factor
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ABSTRACT: The association of the NF-κB p65/p50 dimer with IκBα plays a pivotal role in regulating its nuclear translocation and gene
transcription. In addition, serine phosphorylation at various sites of the p65 subunit has been shown to be important in initiating
transcription. Here we demonstrate that the regulation of nuclear translocation of p65 phosphorylated at serine 536 is not
dependent on IκBα. Stimulation of either Jurkat or normal human T cells resulted in the nuclear translocation of phospho-p65
(Ser536). In addition, the phospho-p65 (Ser536) was not associated with either IκBα or p50, and the nuclear translocation of phospho-p65 (Ser536), but not total p65, was unaffected by the proteosome inhibitor MG-132, which blocks IκB protein degradation and prevents
p65/p50 dimer nuclear translocation. Accordingly, the co-expression of a dominant negative mutant of IκBα blocked the transcriptional
activity mediated by wild type but not the dominant positive p65 mutant (S536D). Furthermore, the transfection of the S536D
form of p65 led to the induction of interleukin-8 transcription following stimulation, whereas the S536A form, which cannot
be phosphorylated at this site, did not. Together, the findings suggest that p65 phosphorylated on serine 536 is not associated
with or regulated by IκBα, that it has a distinct set of target genes, and that it may represent a noncanonical NF-κB pathway
that is independent of IκBα regulation.
Journal of Biological Chemistry 10/2005; 280(41):34538-34547. · 4.77 Impact Factor
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ABSTRACT: Depending on the type of external signals, T cells can initiate multiple intracellular signaling pathways that can be broadly classified into two groups based on their sensitivity to the immunosuppressive drug cyclosporin A (CsA). Interleukin (IL)-12-mediated interferon (IFN)-gamma production by activated T cells has been shown to be CsA-insensitive. In this report, we demonstrate that the IL-12-induced CsA-resistant pathway of IFN-gamma production is sensitive to rapamycin. Rapamycin treatment resulted in the aberrant recruitment of Stat3, Stat4, and phospho-c-Jun to the genomic promoter region resulting in decreased IFN-gamma transcription. IL-12-induced phosphorylation of Stat3 on Ser-727 was affected by rapamycin, which may be due to the effect of rapamycin on the IL-12-induced interaction between mammalian target of rapamycin (mTOR) and Stat3. In accordance with this, reduction in the mTOR protein level by small interfering RNA resulted in suppression of Stat3 phosphorylation and decreased production of IFN-gamma after IL-12 stimulation. These results suggest that mTOR may play a major role in IL-12-induced IFN-gamma production by activated T cells.
Journal of Biological Chemistry 02/2005; 280(2):1037-43. · 4.77 Impact Factor
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ABSTRACT: The mechanisms for "gain-of-function" phenotypes produced by mutant p53s such as enhanced proliferation, resistance to transforming growth factor-beta-mediated growth suppression, and increased tumorigenesis are not known. One theory is that these phenotypes are caused by novel transcriptional regulatory events acquired by mutant p53s. Another explanation is that these effects are a result of an imbalance of functions caused by the retention of some of the wild-type transcriptional regulatory events in the context of a loss of other counterbalancing activities. An analysis of the ability of DNA-binding domain mutants A138P and R175H, and wild-type p53 to regulate the expression levels of 6.9 x 10(3) genes revealed that the mutants retained only <5% of the regulatory activities of the wild-type protein. A138P p53 exhibited mostly retained wild-type regulatory activities and few acquired novel events. However, R175H p53 possessed an approximately equal number of wild-type regulatory events and novel activities. This is the first report that, after examination of the regulation of a large unfocused set of genes, provides data indicating that remaining wild-type transcriptional regulatory functions existing in the absence of counterbalancing activities as well as acquired novel events both contribute to the gain-of-function phenotypes produced by mutant p53s. However, mutant p53s are likely to be distinct in terms of the extent to which each mechanism contributes to their gain-of-function phenotypes.
Cancer Research 11/2004; 64(22):8199-207. · 7.86 Impact Factor
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ABSTRACT: The carefully orchestrated events that result in a protective immune response are coordinated to a large extent by cytokines produced by Th1 and Th2 cell subsets. Th1 cells preferentially produce IL-2 and IFN-gamma, resulting in a cellular response that helps to eliminate infected cells. In contrast, Th2 cells produce IL-4, IL-5, IL-6, and IL-10, stimulating an Ab response that attacks extracellular pathogens, thereby preventing the cells from becoming infected. To elucidate the mechanisms of differential regulation of cytokine genes by these two different subsets of T cells, we established an in vitro differentiation model of freshly isolated human peripheral blood T cells in which IFN-gamma was used as an index gene to study the transcriptional regulation. The data presented here demonstrate that the IFN-gamma promoter undergoes differential methylation during in vitro differentiation: the promoter becomes hypermethylated in Th2 cells, whereas it is hypomethylated in Th1 cells. Hypermethylation in Th2 cells results in chromatin condensation and exclusion of CREB proteins from the IFN-gamma promoter. Treatment with 5-azacytidine, a demethylating agent, causes Th2 cells to reverse histone condensation and enables CREB recruitment to the hypomethylated promoter. This results in the increased production of IFN-gamma. These data indicate the importance of promoter methylation in the regulation of the IFN-gamma gene during differentiation.
The Journal of Immunology 10/2003; 171(5):2510-6. · 5.79 Impact Factor
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ABSTRACT: The consequences of T-cell activation depend exclusively on costimulation during antigen-T-cell receptor interaction. Interaction between the T-cell coreceptor CD28 and its ligand B7 during antigen-antigen receptor engagement results in full activation of T cells, the outcomes of which are proliferation and effector functions. The ability of CD28 to costimulate the production of interleukin-2 (IL-2) explains the importance of this costimulation. The signaling event mediated by CD28 engagement has been proposed to have 2 components: one is sensitive to the immunosuppressive drug cyclosporin A (CsA), and the other one is CsA-resistant. In this report, we demonstrate that the CsA-resistant pathway is sensitive to the immunosuppressive drug rapamycin. Treatment with rapamycin blocked IL-2 production after activation of human peripheral blood T cells with phorbol ester (PMA) and anti-CD28 (CsA-resistant pathway), whereas this drug did not have any effect on PMA plus ionomycin stimulation (CsA-sensitive pathway). The inhibitory effect of rapamycin was on messenger RNA stability and translation, rather than on IL-2 transcription or protein turnover.
Blood 07/2002; 99(12):4517-24. · 9.90 Impact Factor
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Buka Samten, Paritosh Ghosh,
Ae-Kyung Yi,
Stephen E Weis,
David L Lakey,
Rivkah Gonsky,
Usha Pendurthi,
Benjamin Wizel,
Yueru Zhang,
Ming Zhang,
Jianhua Gong,
Marilyn Fernandez,
Hassan Safi,
Ramakrishna Vankayalapati,
Howard A Young,
Peter F Barnes
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ABSTRACT: Mycobacterium tuberculosis-induced IFN-gamma protein and mRNA expression have been shown to be reduced in tuberculosis patients, compared with healthy tuberculin reactors. To determine whether this decrease was associated with reduced activity of the IFN-gamma promoter, we first studied binding of nuclear proteins to the radiolabeled proximal IFN-gamma promoter (-71 to -40 bp), using EMSAs with nuclear extracts of freshly isolated peripheral blood T cells. Nuclear extracts of T cells from most tuberculosis patients showed markedly reduced expression of proteins that bind to the proximal IFN-gamma promoter, compared with findings in nuclear extracts of T cells from healthy tuberculin reactors. These DNA-binding complexes contained CREB proteins, based on competitive EMSAs, supershift assays, and Western blotting with an anti-CREB Ab. Transient transfection of PBLs with a luciferase reporter construct under the control of the IFN-gamma promoter revealed reduced IFN-gamma promoter activity in tuberculosis patients. Transient transfection of Jurkat cells with a dominant-negative CREB repressor plasmid reduced IFN-gamma promoter activity. These data suggest that reduced expression of CREB nuclear proteins in tuberculosis patients results in decreased IFN-gamma promoter activity and reduced IFN-gamma production.
The Journal of Immunology 05/2002; 168(7):3520-6. · 5.79 Impact Factor
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ABSTRACT: Changes in the redox status of cells affect NF-κB and activator protein (AP)-1 nuclear expression and activity. In particular, antioxidants decrease NF-κB and increase AP-1 transcriptional activity, thereby regulating gene expression. In T cells, low concentrations of antioxidants enhance IL-2 and inhibit IL-4 expression. Since NFAT binding sites play an essential role in regulating IL-2 and IL-4 gene transcription, we studied the effects of dithiocarbamates, using the pyrrolidine derivative of dithiocarbamate (PDTC), on the activity of the distinct AP-1-containing IL-2 NFAT and AP-1-less IL-4 NFAT enhancers elements. Consistent with the presence of AP-1 proteins within the IL-2 NFAT complex, PDTC strongly enhanced phorbol 12-myristate 13-acetate/phytohemagglutinin-induced NFAT binding to the IL-2 NFAT enhancer and transcriptional activity of a reporter plasmid driven by this NFAT enhancer. In contrast, the activity of the IL-4 NFp enhancer, which does not bind AP-1, was abolished by PDTC treatment. In the Jurkat T cell line treated with PDTC, co-expression of the Ca2+/calmodulin-dependent phosphatase, calcineurin, completely restored the IL-4 NFp enhancer activity. Our data indicate that calcineurin-mediated NFAT activity is a target for antioxidants and provides new insights into the molecular mechanisms controlling differential cytokine gene expression.
European Journal of Immunology 07/1999; 29(4):1194 - 1201. · 5.10 Impact Factor
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ABSTRACT: Interferon-γ (IFN-γ) is a pleiotropic lymphokine whose production is restricted to activated T cells and NK cells. Along with
other cytokines, IFN-γ gene expression is inhibited by the immunosuppressant cyclosporin A. We have previously identified
an intronic enhancer region (C3) of the IFN-γ gene that binds the NF-κB protein c-Rel and that shows partial DNA sequence
homology with the cyclosporin A-sensitive NFAT binding site and the 3′-half of the NF-κB consensus site. Sequence analysis
of the IFN-γ promoter revealed the presence of two additional C3-related elements (C3-1P and C3-3P). In addition, an NF-κB
site (IFN-γ κB) was identified within the promoter region. Based on this observation, we have analyzed the potential role
of NF-κB and NFAT family members in regulating IFN-γ transcription. Electrophoretic mobility shift assay analysis demonstrated
that after T cell activation, the p50 and p65 NF-κB subunits bind specifically to the newly identified IFN-γ κB and C3-related
sites. In addition, we identified the NFAT proteins as a component of the inducible complexes that bind to the C3-3P site.
Site-directed mutagenesis and transfection studies demonstrate that calcineurin-inducible transcriptional factors enhance
the transcriptional activity of the IFN-γ promoter through the cyclosporin-sensitive C3-3P site, whereas NF-κB proteins functionally
interact with the C3-related sites. In addition, when located downstream to the β-galactosidase gene driven by the IFN-γ promoter,
the intronic C3 site worked in concert with both the IFN-γ κB and the C3-3P site to enhance gene transcription.
These results demonstrate that the coordinate activities of NFAT and NF-κB proteins are involved in the molecular mechanisms
controlling IFN-γ gene transcription.
Journal of Biological Chemistry 11/1997; 272(48):30412-30420. · 4.77 Impact Factor
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ABSTRACT: Background: The carefully orchestrated events that result in a protective immune response are coordinated to a large extent by cytokines produced by T helper 1 (Th1) and T helper 2(Th2) T-cell subsets, which are two arms of the immune system. Th1 cells preferentially produce interleukin 2(IL-2), interferon gamma (IFN γ), and tumor necrosis factor (TNF), resulting in a cellular response that helps to eliminate infected cells. In contrast,Th2 cells produce IL-4, IL-5, IL-6, and IL-10 and stimulate an antibody response that helps to prevent the cells from becoming infected. The clinical progression of several infectious diseases, including human immuno deficiency virus, some types of parasitoses, and tuberculosis, is thought to be associated with the predominance of a Th2-type T-cell response. Recent reports have demonstrated the presence of T cells producing Th2 lymphokines(IL-4, IL-6, and IL-10) in tumor-infiltrating lymphocytes of renal cell carcinoma. Purpose: The purpose of thisstudy was to investigate at themolecular level whether there was anychange in the splenic T cells of mice with progressively growing tumors from a Thl to a Th2 DNA-binding patternor phenotype. Methods: Splenic Tcells from mice bearing renal cell carcinomaor MCA-38 colon carcinoma were tested for cytokine production after in vitro activation. Nuclear extracts of splenic T cells were used for the DNA-binding assay using IFN-γ core promoter region, the kappa B(kB) site from immunoglobulin gene, and the nuclear factor of activated Tcell (NFAT) site from IL-2 gene. Results: Splenic T cells from mice bearing renal cell carcinoma or MCA-38 colon carcinoma preferentially produced Th2 cytokines (i.e., IL-4) upon activation and showed a marked decrease in Th1 cytokine (particularly IFN y) production compared with the production observed in normal splenic T cells. The DNA-binding assay with the IFN-γ core promoter region confirmed the gradual decline in the nuclear transcription factors associated with the Th1 pheno type during tumor progression in both tumor models. Renal cell carcinoma-bearing mice,successfully treated with flavone-8-acetic acid and recombinant human IL-2, showed a reversion to a Th1-likepattern. In addition, nuclear extracts of T cells from tumor-bearing animals showed a Th2-type KB-binding pattern. Moreover, the NFAT complex present in the normal splenic T cells was lost at the later stages of tumor progression; instead, a new complex was present in mice bearing long-term tumors. Conclusion: T cells from tumor-bearing mice lose the Th1 phenotype with progressive tumor growth. [J Natl Cancer Inst 1995;87:1478–83]
JNCI Journal of the National Cancer Institute 11/1995; · 13.76 Impact Factor
