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1.
J Immunol ; 186(2): 697-707, 2011 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-21148798

RESUMO

The reduced efficiency of the mammalian immune system with aging increases host susceptibility to infectious and autoimmune diseases. However, the mechanisms responsible for these pathologic changes are not well understood. In this study, we demonstrate that the bone marrow, blood, and secondary lymphoid organs of healthy aged mice possess increased numbers of immature myeloid cells that are phenotypically similar to myeloid-derived suppressor cells found in lymphoid organs of mice with progressive tumors and other pathologic conditions associated with chronic inflammation. These cells are characterized by the presence of Gr1 and CD11b markers on their surfaces. Gr1(+)CD11b(+) cells isolated from aged mice possess an ability to suppress T cell proliferation/activation and produce heightened levels of proinflammatory cytokines, both constitutively and upon activation, including IL-12, which promotes an excessive production of IFN-γ. IFN-γ priming is essential for excessive proinflammatory cytokine production and the suppressive activities by Gr1(+)CD11b(+) cells from aged mice. These cells suppress T cell proliferation through an NO-dependent mechanism, as depletion of splenic Gr1(+) cells reduces NO levels and restores T cell proliferation. Insights into mechanisms responsible for the proinflammatory and immune suppressive activities of Gr1(+)CD11b(+) cells from aged mice have uncovered a defective PI3K-Akt signaling pathway, leading to a reduced Akt-dependent inactivation of GSK3ß. Our data demonstrate that abnormal activities of the Gr1(+)CD11b(+) myeloid cell population from aged mice could play a significant role in the mechanisms responsible for immune senescence.


Assuntos
Envelhecimento/imunologia , Diferenciação Celular/imunologia , Células Mieloides/citologia , Células Mieloides/imunologia , Envelhecimento/genética , Animais , Antígeno CD11b/biossíntese , Antígeno CD11b/sangue , Antígeno CD11b/genética , Diferenciação Celular/genética , Proliferação de Células , Citocinas/biossíntese , Citocinas/fisiologia , Feminino , Inibidores do Crescimento/biossíntese , Inibidores do Crescimento/genética , Inibidores do Crescimento/fisiologia , Imunofenotipagem , Imunossupressão , Mediadores da Inflamação/metabolismo , Mediadores da Inflamação/fisiologia , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Células Mieloides/metabolismo , Receptores de Quimiocinas/biossíntese , Receptores de Quimiocinas/sangue , Receptores de Quimiocinas/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia
2.
J Clin Invest ; 120(7): 2395-405, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20530874

RESUMO

Hepcidin is a peptide hormone that regulates iron homeostasis and acts as an antimicrobial peptide. It is expressed and secreted by a variety of cell types in response to iron loading and inflammation. Hepcidin mediates iron homeostasis by binding to the iron exporter ferroportin, inducing its internalization and degradation via activation of the protein kinase Jak2 and the subsequent phosphorylation of ferroportin. Here we have shown that hepcidin-activated Jak2 also phosphorylates the transcription factor Stat3, resulting in a transcriptional response. Hepcidin treatment of ferroportin-expressing mouse macrophages showed changes in mRNA expression levels of a wide variety of genes. The changes in transcript levels for half of these genes were a direct effect of hepcidin, as shown by cycloheximide insensitivity, and dependent on the presence of Stat3. Hepcidin-mediated transcriptional changes modulated LPS-induced transcription in both cultured macrophages and in vivo mouse models, as demonstrated by suppression of IL-6 and TNF-alpha transcript and secreted protein. Hepcidin-mediated transcription in mice also suppressed toxicity and morbidity due to single doses of LPS, poly(I:C), and turpentine, which is used to model chronic inflammatory disease. Most notably, we demonstrated that hepcidin pretreatment protected mice from a lethal dose of LPS and that hepcidin-knockout mice could be rescued from LPS toxicity by injection of hepcidin. The results of our study suggest a new function for hepcidin in modulating acute inflammatory responses.


Assuntos
Inflamação/metabolismo , Animais , Peptídeos Catiônicos Antimicrobianos , Transporte Biológico , Proteínas de Transporte de Cátions , Citocinas/metabolismo , Citocinas/farmacologia , Hepcidinas , Interleucina-6/metabolismo , Interleucina-6/farmacologia , Ferro/metabolismo , Ferro/farmacologia , Ferro na Dieta/metabolismo , Ferro na Dieta/farmacologia , Janus Quinase 2/metabolismo , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Fosforilação , Ligação Proteica , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
3.
J Immunol ; 182(7): 4296-305, 2009 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-19299729

RESUMO

The addition of monophosphoryl lipid A, a minimally toxic derivative of LPS, to nonmucosally administered vaccines induced both systemic and mucosal immune responses to coadministered Ags. This was dependent on an up-regulated expression of 1alpha-hydroxylase (CYP27B1, 1alphaOHase), the enzyme that converts 25-hydroxycholecalciferol, a circulating inactive metabolite of vitamin D(3), into 1,25(OH)2D(3) (calcitriol). In response to locally produced calcitriol, myeloid dendritic cells (DCs) migrated from cutaneous vaccination sites into multiple secondary lymphoid organs, including classical inductive sites of mucosal immunity, where they effectively stimulated B and T cell immune responses. The endogenous production of calcitriol by monophosphoryl lipid A-stimulated DCs appeared to be Toll-IL-1R domain-containing adapter-inducing IFN-beta-dependent, mediated through a type 1 IFN-induced expression of 1alphaOHase. Responsiveness to calcitriol was essential to promote the trafficking of mobilized DCs to nondraining lymphoid organs. Collectively, these studies help to expand our understanding of the physiologically important roles played by locally metabolized vitamin D(3) in the initiation and diversification of adaptive immune responses. The influences of locally produced calcitriol on the migration of activated DCs from sites of vaccination/infection into both draining and nondraining lymphoid organs create a condition whereby Ag-responsive B and T cells residing in multiple lymphoid organs are able to simultaneously engage in the induction of adaptive immune responses to peripherally administered Ags as if they were responding to an infection of peripheral or mucosal tissues they were designed to protect.


Assuntos
Adjuvantes Imunológicos/farmacologia , Colecalciferol/metabolismo , Células Dendríticas/imunologia , Receptores Toll-Like/imunologia , Vacinas/imunologia , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/imunologia , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Animais , Linfócitos B/imunologia , Western Blotting , Linfócitos T CD4-Positivos/imunologia , Calcitriol/imunologia , Calcitriol/metabolismo , Movimento Celular/imunologia , Colecalciferol/imunologia , Células Dendríticas/metabolismo , Imunidade nas Mucosas/imunologia , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Lipídeo A/análogos & derivados , Lipídeo A/imunologia , Lipídeo A/farmacologia , Ativação Linfocitária/imunologia , Tecido Linfoide/citologia , Tecido Linfoide/imunologia , Camundongos , Camundongos Transgênicos , Receptores Toll-Like/metabolismo
4.
Infect Immun ; 76(11): 5191-9, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18765736

RESUMO

Immunity conferred by conventional vaccines is restricted to a narrow range of closely related strains, highlighting the unmet medical need for the development of vaccines that elicit protection against multiple pathogenic serotypes. Here we show that a Salmonella bivalent vaccine comprised of strains that lack and overproduce DNA adenine methylase (Dam) conferred cross-protective immunity to salmonella clinical isolates of human and animal origin. Protective immunity directly correlated with increased levels of cross-reactive opsonizing antibodies and memory T cells and a diminished expansion of myeloid-derived suppressor cells (MDSCs) that are responsible for the immune suppression linked to several conditions of host stress, including chronic microbial infections, traumatic insults, and many forms of cancer. Further, aged mice contained increased numbers of MDSCs and were more susceptible to Salmonella infection than young mice, suggesting a role for these cells in the immune declines associated with the natural aging process. These data suggest that interventions capable of reducing MDSC presence and activities may allow corresponding increases in B- and T-cell stimulation and benefit the ability of immunologically diverse populations to be effectively vaccinated as well as reducing the risk of susceptible individuals to infectious disease.


Assuntos
Anticorpos Antibacterianos/imunologia , Células Mieloides/imunologia , Salmonelose Animal/prevenção & controle , Vacinas contra Salmonella/imunologia , Salmonella/imunologia , Envelhecimento/imunologia , Animais , Reações Cruzadas , Células HeLa , Humanos , Memória Imunológica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Linfócitos T/imunologia
5.
Appl Environ Microbiol ; 74(6): 1757-66, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18245251

RESUMO

The global trend toward intensive livestock production has led to significant public health risks and industry-associated losses due to an increased incidence of disease and contamination of livestock-derived food products. A potential factor contributing to these health concerns is the prospect that selective pressure within a particular host may give rise to bacterial strain variants that exhibit enhanced fitness in the present host relative to that in the parental host from which the strain was derived. Here, we assessed 184 Salmonella enterica human and animal clinical isolates for their virulence capacities in mice and for the presence of the Salmonella virulence plasmid encoding the SpvB actin cytotoxin required for systemic survival and Pef fimbriae, implicated in adherence to the murine intestinal epithelium. All (21 of 21) serovar Typhimurium clinical isolates derived from animals were virulent in mice, whereas many (16 of 41) serovar Typhimurium isolates derived from human salmonellosis patients lacked this capacity. Additionally, many (10 of 29) serovar Typhimurium isolates derived from gastroenteritis patients did not possess the Salmonella virulence plasmid, in contrast to all animal and human bacteremia isolates tested. Lastly, among serovar Typhimurium isolates that harbored the Salmonella virulence plasmid, 6 of 31 derived from human salmonellosis patients were avirulent in mice, which is in contrast to the virulent phenotype exhibited by all the animal isolates examined. These studies suggest that Salmonella isolates derived from human salmonellosis patients are distinct from those of animal origin. The characterization of these bacterial strain variants may provide insight into their relative pathogenicities as well as into the development of treatment and prophylactic strategies for salmonellosis.


Assuntos
Salmonella enterica/genética , Salmonella enterica/patogenicidade , ADP Ribose Transferases/genética , Animais , Gastroenterite/microbiologia , Humanos , Mucosa Intestinal/microbiologia , Camundongos , Reação em Cadeia da Polimerase , Infecções por Salmonella/microbiologia , Salmonella enterica/classificação , Sorotipagem , Virulência/genética , Fatores de Virulência/genética
6.
Vaccine ; 26(5): 601-13, 2008 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-18178294

RESUMO

Cathelicidin production by human myeloid cells stimulated through toll-like receptor (TLR) 2/1, the migration of human CD8+ T cells to inflamed skin sites, and the ability of murine dendritic cells (DCs) to migrate from skin sites of vaccination to mucosal lymphoid organs all occur via calcitriol-dependent mechanisms. Herein, we report that murine DCs exposed to TLR3/TLR4 ligands upregulate their expression of 1 alpha-hydroxylase, the enzyme that converts circulating 25(OH)D3 to calcitriol, the active form of vitamin D3. TLR3/TLR4 ligands injected subcutaneously affect DC migration in vivo, allowing their trafficking to both draining and non-draining systemic and mucosal lymphoid organs. Subcutaneously delivered vaccines containing TLR3/TLR4 ligands and antigen stimulate the induction of both systemic and mucosal immune responses. Vaccines containing TLR9 ligands fail to stimulate 1 alpha-hydroxylase protein expression, are incapable of redirecting DC migration into Peyer's patches and do not induce mucosal immune responses. These findings support a hypothesis that active metabolites of vitamin D3 produced locally are able to affect various aspects of innate and acquired immune responses.


Assuntos
Calcitriol/metabolismo , Colecalciferol/metabolismo , Células Dendríticas/fisiologia , Receptor 3 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Vacinação , Animais , Proteínas de Bactérias/administração & dosagem , Proteínas de Bactérias/imunologia , Movimento Celular , Células Cultivadas , Hidrolases/metabolismo , Imunidade nas Mucosas , Injeções Subcutâneas , Ligantes , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Transgênicos , Nódulos Linfáticos Agregados/imunologia , Receptores de Antígenos de Linfócitos T/deficiência , Receptores de Antígenos de Linfócitos T/genética , Regulação para Cima
7.
J Immunol ; 179(9): 6325-35, 2007 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-17947710

RESUMO

11beta-Hydroxysteroid dehydrogenase type 1 (11betaHSD1) performs end-organ metabolism of glucocorticoids (GCs) by catalyzing the conversion of C(11)-keto-GCs to C(11)-hydroxy-GCs, thereby generating activating ligands for the GC receptor. In this study, we report that 11betaHSD1(-/-) mice are more susceptible to endotoxemia, evidenced by increased weight loss and serum TNF-alpha, IL-6, and IL-12p40 levels following LPS challenge in vivo. Peritoneal and splenic macrophage (splnMphi) from these genetically altered mice overproduce inflammatory cytokines following LPS stimulation in vitro. Inflammatory cytokine overexpression by 11betaHSD1(-/-) splnMphi results from an increased activation of NF-kappaB- and MAPK-signaling cascades and an attenuated PI3K-dependent Akt activation. The expression of SHIP1 is augmented in 11betaHSD1(-/-) Mphi and contributes to inflammatory cytokine production because overexpression of SHIP1 in primary bone marrow Mphi (BMMphi) leads to a similar type of hyperresponsiveness to subsequent LPS stimulation. 11betaHSD1(+/+) and 11betaHSD1(-/-) BMMphi responded to LPS similarly. However, 11betaHSD1(-/-) BMMphi derived in the presence of elevated GC levels up-regulated SHIP1 expression and increased their capacity to produce inflammatory cytokines following their activation with LPS. These observations suggest the hyperresponsiveness of 11betaHSD1(-/-) splnMphi results from myeloid cell differentiation in the presence of moderately elevated GC levels found within 11betaHSD1(-/-) mice. GC-conditioning of BMMphi enhanced SHIP1 expression via up-regulation of bioactive TGF-beta. Consistently, TGF-beta protein expression was increased in unstimulated CD11b(-) cells residing in the BM and spleen of 11betaHSD1(-/-) mice. Our results suggest that modest elevations in plasma GC levels can modify the LPS responsiveness of Mphi by augmenting SHIP1 expression through a TGF-beta-dependent mechanism.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Regulação para Cima/efeitos dos fármacos , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/deficiência , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/enzimologia , Peso Corporal , Medula Óssea/metabolismo , Células Cultivadas , Ativação Enzimática , Glucocorticoides/metabolismo , Inositol Polifosfato 5-Fosfatases , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Vison , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sensibilidade e Especificidade , Transdução de Sinais , Baço/metabolismo
8.
J Bacteriol ; 189(13): 4708-17, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17468250

RESUMO

Salmonella enterica serovar Typhimurium that lacks the DNA adenine methylase (Dam) ectopically expresses multiple genes that are preferentially expressed during infection, is attenuated for virulence, and confers heightened immunity in vaccinated hosts. The safety of dam mutant Salmonella vaccines was evaluated by screening within infected mice for isolates that have an increased capacity to cause disease relative to the attenuated parental strain. Since dam mutant strains are sensitive to the DNA base analog 2-aminopurine (2-AP), we screened for 2-AP-resistant (2-AP(r)) isolates in systemic tissues of mice infected with dam mutant Salmonella. Such 2-AP(r) derivatives were isolated following intraperitoneal but not oral administration and were shown to be competent for infectivity via intraperitoneal but not oral infection of naïve mice. These 2-AP(r) derivatives were deficient in methyl-directed mismatch repair and were resistant to nitric oxide, yet they retained the bile-sensitive phenotype of the parental dam mutant strain. Additionally, introduction of a mutH null mutation into dam mutant cells suppressed the inherent defects in intraperitoneal infectivity and nitric oxide resistance, as well as overexpression of SpvB, an actin cytotoxin required for Salmonella systemic survival. These data suggest that restoration of intraperitoneal virulence of dam mutant strains is associated with deficiencies in methyl-directed mismatch repair that correlate with the production of systemically related virulence functions.


Assuntos
Reparo de Erro de Pareamento de DNA , Mutação , Salmonelose Animal/genética , Salmonella/genética , DNA Metiltransferases Sítio Específica (Adenina-Específica)/genética , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Ácidos e Sais Biliares/farmacologia , Western Blotting , Farmacorresistência Bacteriana/genética , Fígado/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Boca/microbiologia , Mucosa Bucal/microbiologia , Óxido Nítrico/farmacologia , Cavidade Peritoneal/microbiologia , Reação em Cadeia da Polimerase , Salmonella/patogenicidade , Salmonelose Animal/metabolismo , Salmonelose Animal/microbiologia , DNA Metiltransferases Sítio Específica (Adenina-Específica)/metabolismo , Baço/microbiologia , Transcrição Genética , Virulência/genética
9.
J Immunol ; 178(4): 2517-26, 2007 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-17277160

RESUMO

The immunomodulatory effects of glucocorticoids (GCs) have been described as bimodal, with high levels of GCs exerting immunosuppressive effects and low doses of GCs being immunopermissive. While the mechanisms used by GCs to achieve immunosuppression have been investigated intensely, the molecular mechanisms underlying the permissive effects of GCs remain uncharacterized. Herein, we demonstrate that GC conditioning during the differentiation of myeloid progenitors into macrophages (Mphis) results in their enhanced LPS responsiveness, demonstrated by an overexpression of the inflammatory cytokines TNF-alpha, IL-6, and IL-12. Inflammatory cytokine overexpression resulted from an increased activation of NF-kappaB and the MAPK signaling cascade and a reduced activation of the PI3K-Akt pathway following LPS stimulation. GC conditioning during Mphi differentiation induced an increase in the expression of SHIP1, a phosphatase that negatively regulates the PI3K signaling pathway. Small interfering RNA-mediated knockdown of SHIP1 expression increased PI3K-dependent Akt activation and subsequently decreased inflammatory cytokine expression, suggesting GC-mediated up-regulation of SHIP1 expression is responsible for the augmentation in inflammatory cytokine production following LPS stimulation. We also show that splenic Mphis purified from normal mice that were implanted with timed-release GC pellets exhibited an enhanced LPS responsiveness and increased SHIP1 expression, indicating that GCs can regulate SHIP1 expression in vivo. Our results suggest that minor fluctuations in physiological levels of endogenous GCs can program endotoxin-responsive hemopoietic cells during their differentiation by regulating their sensitivity to stimulation.


Assuntos
Glucocorticoides/farmacologia , Células Progenitoras Mieloides/imunologia , Fosfatidilinositol 3-Quinases/imunologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/imunologia , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Células Progenitoras Mieloides/enzimologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/imunologia , Receptor 4 Toll-Like/metabolismo
10.
Vaccine ; 25(7): 1236-49, 2007 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-17092617

RESUMO

The mucosal immune system provides the host with a first line of adaptive immune defense against invasion by many species of pathogenic microorganisms and their secreted products. Calcitriol, the active form of Vitamin D3 (VD3), promotes the induction of mucosal immunity in mice when added to subcutaneously administered vaccine formulations. Dendritic cells (DCs) activated at vaccination sites where VD3 is present gain the capacity to bypass sequestration in the draining lymph node and traffic to the Peyer's Patches (PP) of immunized animals. By employing protocols that allow the effective tracking of endogenous or adoptively transferred myeloid DCs in vivo, we found that VD3 influences on the trafficking of fully differentiated immature DCs were temporary, and occur without negative effects to antigen processing or peptide presentation to CD4+ T cells. In contrast, DCs differentiated from hematopoietic precursors in the presence of VD3 (conditioned DCs), were markedly compromised in their antigen presenting properties, while manifesting clear alterations to their trafficking properties in vivo. Similar to the recent finding of VD3-mediated enhancement of innate immune protection, our findings suggest that VD3 could also play an important role in controlling the types of immune effector responses elicited subsequent to either infection or vaccination.


Assuntos
Adjuvantes Imunológicos , Apresentação do Antígeno/efeitos dos fármacos , Apresentação do Antígeno/imunologia , Colecalciferol/farmacologia , Células Dendríticas/imunologia , Células Mieloides/imunologia , Animais , Células da Medula Óssea/imunologia , Linfócitos T CD4-Positivos/imunologia , Quimiotaxia de Leucócito/imunologia , Células Dendríticas/efeitos dos fármacos , Feminino , Imunidade nas Mucosas/imunologia , Imunoterapia Adotiva , Tecido Linfoide/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Transgênicos , Células Mieloides/efeitos dos fármacos , Receptores CCR7 , Receptores de Quimiocinas/biossíntese , Receptores de Quimiocinas/genética , Pele/citologia , Pele/imunologia
11.
J Immunol ; 174(2): 879-89, 2005 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-15634910

RESUMO

The 11beta-hydroxysteroid dehydrogenase (11beta-HSD) enzymes control the interconversion of active glucocorticoids (GCS) and their inactive 11-keto metabolites, a process commonly referred to as the cortisone/cortisol shuttle. Although the prereceptor metabolism of GCS by 11beta-HSD is well documented in a variety of cells and tissues, it has not yet been carefully investigated in the major cell types of the immune system. In this study, we demonstrate that 11beta-HSD1 transcripts, protein, and enzyme activities are actively expressed in murine CD4(+), CD8(+), and B220(+) lymphocytes, as well as CD11c(+) dendritic cells. Only reductase activity was observed in living cells, evidenced by the restricted conversion of cortisone to cortisol. Activation of CD4(+) T cells increased their 11beta-HSD1 activity, as did their polarization into Th1 or Th2 cells. CD4(+) T cells isolated from aged donors (>16 mo) had increased 11beta-HSD1 protein and an elevated capacity to convert cortisone to cortisol. The GCS generated in murine CD4(+) T cells from their inactive 11-keto metabolites could activate the GCS receptor, demonstrated by an up-regulation of IL-7Ralpha and GCS-induced leucine zipper gene expression. The presence of a functional 11beta-HSD1 provides lymphocytes with a novel intracrine regulatory mechanism that could influence such processes as lymphocyte development, effector function, and susceptibility to apoptosis. Thus, the presence of 11beta-HSD1 provides an additional means to facilitate GCS influences over lymphocyte activities, uncoupled from the plasma concentration of GCS.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/biossíntese , Glucocorticoides/metabolismo , Linfócitos T/enzimologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/deficiência , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , Envelhecimento/imunologia , Envelhecimento/metabolismo , Animais , Linfócitos T CD4-Positivos/enzimologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linhagem Celular , Células Cultivadas , Feminino , Glucocorticoides/biossíntese , Ligantes , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Oxirredutases/metabolismo , RNA Mensageiro/biossíntese , Receptores de Antígenos de Linfócitos T/fisiologia , Receptores de Glucocorticoides/metabolismo , Receptores de Glucocorticoides/fisiologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Células Th1/enzimologia , Células Th1/imunologia , Células Th1/metabolismo , Regulação para Cima/imunologia
12.
Antioxid Redox Signal ; 5(5): 537-48, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-14580308

RESUMO

The elderly suffer impairments to their immune system, evidenced by higher susceptibility to infections, cancer, and many diseases believed to be autoimmune in nature. A dysregulated overexpression of many proinflammatory cytokines also occurs with aging, as does the synthesis of enzymes that control expression of inflammatory lipid mediators and reactive oxygen species. An inappropriate activation of redox-controlled transcription factors, like nuclear factor-kappaB, occurs in many tissues from aged donors, and has been linked to excesses in cellular oxidative stress. Recently, the peroxisome proliferator-activated receptor-alpha (PPARalpha) has been evaluated for its effects on inflammatory and adaptive immune processes. PPARalpha provides redox-balancing influences on various lymphoid cell types and their inducible responses. We recently discovered that PPARalpha transiently suppresses the transcription of gamma-interferon (IFNgamma) by inhibiting the induction of T-bet. We now report that PPARalpha expression in CD4+ T cells is affected by the aging process. Lower PPARalpha levels are present in aged CD4+ T cells, and appear responsible for the suppressed interleukin-2 and exaggerated IFNgamma responses by these cells. Restoration of PPARalpha, T-bet, interleukin-2, and IFNgamma responses was found in T cells from aged animals supplemented with vitamin E, suggesting that interventions that focus on restoring redox balance might benefit the ailing aged immune system.


Assuntos
Envelhecimento/imunologia , Linfócitos T CD4-Positivos/fisiologia , Interferon gama/metabolismo , Interleucina-2/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Administração Oral , Fatores Etários , Animais , Anticorpos/farmacologia , Western Blotting , Antígenos CD28/imunologia , Complexo CD3/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Expressão Gênica , Selectina L/análise , Selectina L/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Ovalbumina/imunologia , Oxirredução , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Receptores Citoplasmáticos e Nucleares/genética , Proteínas com Domínio T , Fatores de Transcrição/genética , Vitamina E/farmacologia
13.
J Immunol ; 171(1): 196-203, 2003 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-12816998

RESUMO

Expression of the nuclear hormone receptor peroxisome proliferator-activated receptor alpha (PPARalpha) in resting lymphocytes was recently established, although the physiologic role(s) played by this nuclear hormone receptor in these cell types remains unresolved. In this study, we used CD4(+) T cells isolated from PPARalpha(-/-) and wild-type mice, as well as cell lines that constitutively express PPARalpha, in experiments designed to evaluate the role of this hormone receptor in the regulation of T cell function. We report that activated CD4(+) T cells lacking PPARalpha produce increased levels of IFN-gamma, but significantly lower levels of IL-2 when compared with activated wild-type CD4(+) T cells. Furthermore, we demonstrate that PPARalpha regulates the expression of these cytokines by CD4(+) T cells in part, through its ability to negatively regulate the transcription of T-bet. The induction of T-bet expression in CD4(+) T cells was determined to be positively influenced by p38 mitogen-activated protein (MAP) kinase activation, and the presence of unliganded PPARalpha effectively suppressed the phosphorylation of p38 MAP kinase. The activation of PPARalpha with highly specific ligands relaxed its capacity to suppress p38 MAP kinase phosphorylation and promoted T-bet expression. These results demonstrate a novel DNA-binding independent and agonist-controlled regulatory influence by the nuclear hormone receptor PPARalpha.


Assuntos
Regulação para Baixo/genética , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Receptores Citoplasmáticos e Nucleares/fisiologia , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Fatores de Transcrição/fisiologia , Transcrição Genética , Animais , Butiratos/metabolismo , Butiratos/farmacologia , Linfócitos T CD4-Positivos/enzimologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Regulação para Baixo/imunologia , Ativação Enzimática/genética , Ativação Enzimática/imunologia , Humanos , Interferon gama/antagonistas & inibidores , Interferon gama/biossíntese , Interleucina-2/antagonistas & inibidores , Interleucina-2/biossíntese , Células Jurkat , Ligantes , Ativação Linfocitária/genética , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Compostos de Fenilureia/metabolismo , Compostos de Fenilureia/farmacologia , Fosforilação , RNA Mensageiro/biossíntese , Receptores Citoplasmáticos e Nucleares/deficiência , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de Interferon/fisiologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Proteínas com Domínio T , Fatores de Tempo , Fatores de Transcrição/biossíntese , Fatores de Transcrição/deficiência , Fatores de Transcrição/metabolismo , Transcrição Genética/imunologia , Regulação para Cima/genética , Regulação para Cima/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno
14.
Cancer Res ; 62(23): 6870-8, 2002 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-12460901

RESUMO

The transcription factor nuclear factor kappaB (NFkappaB) is constitutively active in many types of cancercells and regulates the expression of several antiapoptotic genes. Previous studies demonstrated a role for the inhibition of NFkappaB in cancer therapyusing a transgenic approach in mice. We found that NFkappaB was transiently activated much greater than background constitutive levels during colon cancer cell readhesion, which rendered the readhering colon cancer cells exquisitely susceptible to apoptosis in the presence of soluble NFkappaB inhibitors. These compounds greatly reduced colon cancer cell implantation in an in vivo seeding model of metastasis. The ability of soluble NFkappaB inhibitors to significantly induce apoptosis of readherent colon cancer cells makes them prospective candidates for preventing colon cancer metastasis.


Assuntos
Anti-Infecciosos/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias do Colo/patologia , NF-kappa B/antagonistas & inibidores , Nitrilos , Compostos Orgânicos , Sulfonas , Neoplasias Abdominais/secundário , Animais , Adesão Celular/efeitos dos fármacos , Adesão Celular/fisiologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/cirurgia , Feminino , Humanos , Camundongos , Camundongos Nus , NF-kappa B/fisiologia , Inoculação de Neoplasia , Transplante de Neoplasias , Transplante Heterólogo , Células Tumorais Cultivadas
15.
Nat Rev Immunol ; 2(10): 748-59, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12360213

RESUMO

Lipids and lipid metabolism have well-documented regulatory effects on inflammatory processes. Recent work has highlighted the role of the peroxisome proliferator-activated receptors (PPARs)--a subset of the nuclear-hormone-receptor superfamily that are activated by various lipid species--in regulating inflammatory responses. Here, we describe how the PPARs, through their interactions with transcription factors and other cell-signalling systems, have important regulatory roles in innate and adaptive immunity.


Assuntos
Inflamação/etiologia , Receptores Citoplasmáticos e Nucleares/imunologia , Receptores Citoplasmáticos e Nucleares/fisiologia , Fatores de Transcrição/imunologia , Fatores de Transcrição/fisiologia , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Humanos , Imunidade Inata , Inflamação/tratamento farmacológico , Ligantes , Modelos Imunológicos , Receptores Citoplasmáticos e Nucleares/química , Transdução de Sinais , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fatores de Transcrição/química , Ativação Transcricional
16.
Proc Nutr Soc ; 61(3): 363-9, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12296295

RESUMO

Peroxisome proliferator-activated receptor (PPAR) represents an important member of the nuclear hormone receptor superfamily that can be activated by a variety of natural fatty acids, some of their metabolites and by commonly-used anti-lipidaemic drugs. We recently demonstrated PPAR expression in T lymphocytes, where it controls the initiation of transcription of T-box expressed in T-cells (T-bet) independent of added agonist. T-bet is an activation-inducible transcription factor regulator of interleukin 2 (suppression) and interferon (stimulation) synthesis. A suppressed ability to produce interleukin 2 and an enhanced production of interferon occurs in activated T-cells from PPAR-/- mice, as well as in T-cells from wild-type aged animals whose lymphocytes express lowered basal levels of PPAR. The dysregulated expression and/or function of cytokines, glucocorticoids or leptin that occurs with advanced age could all be responsible for the reduced expression of PPAR. Dietary supplementation of aged mice with vitamin E, or supplementation with known agonists of PPAR, was associated with elevation of lymphocyte expression of this nuclear hormone receptor, restoration of control over T-bet expression and elimination of the dysregulated production of interleukin 2 and interferon following lymphocyte activation. Interleukin 2 and interferon play very important roles in the initiation and/or regulation of immune, inflammatory and autoimmune disease states. Thus, the mechanisms that control the timing, magnitude and duration of specific cytokine production by activated T lymphocytes need clarification before appropriate nutritional or therapeutic strategies can be devised to treat disease conditions where cytokine expression and/or activities are deemed to be dysregulated and responsible.


Assuntos
Envelhecimento/fisiologia , Inflamação/fisiopatologia , Receptores Citoplasmáticos e Nucleares/fisiologia , Linfócitos T/fisiologia , Fatores de Transcrição/fisiologia , Idoso , Envelhecimento/imunologia , Animais , Regulação da Expressão Gênica , Humanos , Interferon gama/biossíntese , Interleucina-2/biossíntese , Linfócitos T/imunologia
17.
Vaccine ; 20(16): 2116-30, 2002 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-11972981

RESUMO

It has been reported that common mucosal immunity can be efficiently induced in mice following immunization through the skin with vaccine formulations containing either the active form of vitamin D, or chemical agents capable of locally enhancing cyclic adenosine monophosphate levels. Herein, we report that exposure of skin to ultraviolet radiation B (UVB) can be employed as a means to alter systemic humoral immune responses and to promote the induction of mucosal immunity to protein antigens delivered into UVB-exposed skin sites. Our data indicates that the skin, as a vaccination site, can be manipulated to allow efficient induction of common mucosal and systemic immune responses.


Assuntos
Formação de Anticorpos , Imunidade nas Mucosas , Pele/imunologia , Pele/efeitos da radiação , Vacinas/imunologia , Administração Cutânea , Animais , Citocinas/biossíntese , Células Dendríticas/imunologia , Relação Dose-Resposta Imunológica , Feminino , Imunização , Imunoglobulina G/sangue , Imunoglobulina G/classificação , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H
18.
J Biol Chem ; 277(9): 6838-45, 2002 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-11726654

RESUMO

Peroxisome proliferator-activated receptors (PPARs) are transcription factors that belong to the nuclear hormone receptor superfamily. PPARalpha and PPARgamma ligands have been demonstrated to exert anti-inflammatory activities in macrophages by repressing the activities of several transcription factors. PPARgamma is expressed in T lymphocytes and may play a role in cytokine production, cellular proliferation, and susceptibility to apoptosis. Herein, we demonstrate that T and B lymphocytes constitutively express PPARalpha. PPARalpha represents the predominant isoform expressed in lymphocytes, whereas PPARgamma dominates in all cell types of the myeloid lineage. PPARalpha expression was down-regulated following T-cell activation while PPARgamma expression increased under the same activating conditions. PPARalpha expression in T cells may be regulated by microenvironmental factors, because Peyer's patch T cells expressed far greater levels of PPARalpha than T cells isolated from peripheral lymphoid organs. Exposure to specific ligand determined that PPARalpha in lymphocytes can effectively transactivate a peroxisome proliferator response element reporter construct. PPARalpha's ability to regulate endogenous genes, however, required treatment with histone deacetylase inhibitors. Finally, ligand activation of lymphocyte PPARalpha antagonized NF-kappaB. Our observation that a functional PPARalpha exists within T cells and B lymphocytes suggests an expanding role for this nuclear receptor in cells of the immune system.


Assuntos
Núcleo Celular/metabolismo , Linfócitos/metabolismo , Receptores Citoplasmáticos e Nucleares/química , Receptores Citoplasmáticos e Nucleares/metabolismo , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo , Animais , Linfócitos B/metabolismo , Butiratos/farmacologia , Divisão Celular , Linhagem Celular , Dexametasona/farmacologia , Relação Dose-Resposta a Droga , Regulação para Baixo , Ensaio de Imunoadsorção Enzimática , Feminino , Genes Reporter , Histona Desacetilases/metabolismo , Humanos , Interferon gama/biossíntese , Ligantes , Luciferases/metabolismo , Linfócitos/enzimologia , Macrófagos/metabolismo , Camundongos , Camundongos Transgênicos , Microscopia de Fluorescência , Compostos de Fenilureia/farmacologia , Ligação Proteica , Isoformas de Proteínas , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T/metabolismo , Fatores de Tempo , Distribuição Tecidual , Transcrição Genética , Transfecção , Regulação para Cima
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