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1.
Artigo em Inglês | MEDLINE | ID: mdl-31917615

RESUMO

RATIONALE: Vascular remodeling, including smooth muscle cell hypertrophy and proliferation, is the key pathological feature of pulmonary arterial hypertension (PAH). Prostaglandin (PG) I2 analogs (baraprost, iloprost, and treprostinil) are effective in the treatment of PAH. Of note, the clinically favorable effects of treprostinil in severe PAH may be attributable to concomitant activation of PGD2 receptor subtype 1 (DP1). OBJECTIVES: To study the role of DP1 in the progression of PAH and its underlying mechanism. METHODS AND RESULTS: DP1 expression was downregulated in hypoxia-treated PASMCs and in pulmonary arteries (PAs) from rodent PAH models and idiopathic PAH patients. DP1 deletion exacerbated PA remodeling in hypoxia-induced PAH, whereas pharmacological activation or forced expression of DP1 receptor had the opposite effect in different rodent models. DP1 deficiency promoted PASMC hypertrophy and proliferation in response to hypoxia via induction of mammalian target of rapamycin complex (mTORC) 1 activity. Rapamycin, an inhibitor of mTORC1, alleviated the hypoxia-induced exacerbation of PAH in DP1-/- mice. DP1 activation facilitated raptor dissociation from mTORC1 complex and suppressed mTORC1 activity through protein kinase A (PKA)-dependent phosphorylation of raptor at Ser791. Moreover, treprostinil treatment blocked the progression of hypoxia-induced PAH in mice in part by targeting DP1 receptor. CONCLUSION: DP1 activation attenuates hypoxia-induced PA remodeling and PAH through PKA-mediated dissociation of raptor from the mTORC1 complex. These results suggest that DP1 receptor may serve as a therapeutic target for the management of PAH.

2.
Arterioscler Thromb Vasc Biol ; 39(4): e130-e145, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30676070

RESUMO

Objective- Macrophages participate in the pathogenesis of pulmonary arterial hypertension (PAH). Lgmn (Legumain), a newly discovered cysteine proteinase belonging to the C13 peptidase family, is primarily expressed in macrophages; however, its roles in PAH remain unknown. Approach and Results- Herein, Lgmn was upregulated in lung tissues of PAH mice subjected to hypoxia plus SU5416 and PAH rats challenged with monocrotaline. Global Lgmn ablation and macrophage-specific ablation alleviated PAH compared with wild-type mice, evident from a reduction in right ventricular systolic pressure, the ratio of the right ventricular wall to the left ventricular wall plus the septum, the pulmonary vascular media thickness, and pulmonary vascular muscularization. Increased expression of ECM (extracellular matrix) proteins was correlated with MMP (matrix metalloproteinase)-2 activation and TGF (transforming growth factor)-ß1 signaling in the PAs. Although Lgmn did not affect inflammatory cell infiltration and PA smooth muscle cell proliferation, it drove increased the synthesis of ECM proteins via MMP-2 activation. MMP-2 hydrolyzed the TGF-ß1 precursor to the active form. An Lgmn-specific inhibitor markedly ameliorated PAH. Clinically, serum Lgmn levels were closely associated with the severity of idiopathic PAH. Conclusions- Our results indicate that Lgmn inhibition could be an effective strategy for preventing or delaying PAH.


Assuntos
Cisteína Endopeptidases/fisiologia , Hipertensão Pulmonar/enzimologia , Macrófagos/enzimologia , Metaloproteinase 2 da Matriz/fisiologia , Fator de Crescimento Transformador beta1/fisiologia , Animais , Inibidores de Caspase/farmacologia , Cisteína Endopeptidases/deficiência , Proteínas da Matriz Extracelular/metabolismo , Feminino , Seguimentos , Humanos , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/prevenção & controle , Hipóxia/enzimologia , Indóis/toxicidade , Inflamação , Pulmão/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Monocrotalina/toxicidade , Pirróis/toxicidade , Ratos , Índice de Gravidade de Doença , Transdução de Sinais , Remodelação Vascular/fisiologia
3.
J Exp Med ; 215(8): 2175-2195, 2018 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-29970474

RESUMO

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by progressive pulmonary artery (PA) remodeling. T helper 2 cell (Th2) immune response is involved in PA remodeling during PAH progression. Here, we found that CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cell) expression was up-regulated in circulating CD3+CD4+ T cells in patients with idiopathic PAH and in rodent PAH models. CRTH2 disruption dramatically ameliorated PA remodeling and pulmonary hypertension in different PAH mouse models. CRTH2 deficiency suppressed Th2 activation, including IL-4 and IL-13 secretion. Both CRTH2+/+ bone marrow reconstitution and CRTH2+/+ CD4+ T cell adoptive transfer deteriorated hypoxia + ovalbumin-induced PAH in CRTH2-/- mice, which was reversed by dual neutralization of IL-4 and IL-13. CRTH2 inhibition alleviated established PAH in mice by repressing Th2 activity. In culture, CRTH2 activation in Th2 cells promoted pulmonary arterial smooth muscle cell proliferation through activation of STAT6. These results demonstrate the critical role of CRTH2-mediated Th2 response in PAH pathogenesis and highlight the CRTH2 receptor as a potential therapeutic target for PAH.


Assuntos
Hipertensão Pulmonar/imunologia , Ativação Linfocitária/imunologia , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Células Th2/imunologia , Transferência Adotiva , Adulto , Animais , Anticorpos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Proliferação de Células/efeitos dos fármacos , Quimera , Doença Crônica , Modelos Animais de Doenças , Feminino , Deleção de Genes , Humanos , Hipertensão Pulmonar/fisiopatologia , Hipóxia/complicações , Hipóxia/fisiopatologia , Imunidade/efeitos dos fármacos , Indóis , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/fisiopatologia , Masculino , Camundongos , Ovalbumina , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiopatologia , Pirróis , Receptores Imunológicos/deficiência , Receptores de Prostaglandina/deficiência , Fator de Transcrição STAT6/metabolismo , Regulação para Cima/efeitos dos fármacos
4.
Cardiovasc Res ; 114(5): 703-712, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29415171

RESUMO

Aims: Cardiac myofibroblasts (CMFs) play a crucial role in the progression of pathological fibrotic cardiac remodelling. The expression of osteoglycin (OGN) is increased in diseased hearts; however, the role of OGN in pathological cardiac remodelling is not understood. Here, we sought to determine the effect of OGN on cardiac interstitial fibrosis and investigate the molecular mechanisms of OGN in CMF activation and matrix production. Methods and results: We found that OGN expression was significantly upregulated in mouse hearts in response to chronic 14-day angiotensin II (Ang II) infusion. Mice lacking OGN (OGN-/-) exhibited enhanced cardiac interstitial fibrosis and significantly more severe cardiac dysfunction following Ang II infusion compared to wild-type mice. OGN deficiency did not alter blood pressure, nor had effect on transforming growth factor-beta signalling activation, but presented with increased proliferative activity in hearts. In vitro studies with isolated CMFs revealed that OGN deficiency significantly increased proliferation and migration and enhanced the transactivation of epidermal growth factor receptor (EGFR) signalling by Ang II. On the other hand, OGN overexpression in CMFs decreased their proliferation and migration via reducing EGFR activation. Overexpression of OGN also suppressed the shedding of membrane anchored EGFR ligand. Moreover, OGN was found to interact with a lysophosphatidic acid (LPA) receptor isoform 3 and thus to attenuate EGFR transactivation through blocking cell surface translocation of membrane type 1 matrix metalloproteinase (MT1-MMP) and subsequent pro-MMP-2 activation in a Ras homolog gene family, member A (RhoA)/Rho-associated, coiled-coil containing protein kinase (ROCK)-dependent manner. Conclusion: These findings suggest that OGN negatively regulates cardiac fibrotic remodelling by attenuating CMF proliferation and migration through LPA3-mediated and Rho/ROCK-dependent inhibition of MT1-MMP translocation, MMP2 activation and EGFR transactivation.


Assuntos
Cardiomegalia/enzimologia , Proliferação de Células , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Miofibroblastos/enzimologia , Receptores de Ácidos Lisofosfatídicos/metabolismo , Remodelação Ventricular , Angiotensina II , Animais , Cardiomegalia/induzido quimicamente , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Movimento Celular , Células Cultivadas , Modelos Animais de Doenças , Receptores ErbB/metabolismo , Fibrose , Hipertensão/induzido quimicamente , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Peptídeos e Proteínas de Sinalização Intercelular/genética , Metaloproteinase 14 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/patologia , Miofibroblastos/patologia , Receptor Cross-Talk , Transdução de Sinais , Proteínas rho de Ligação ao GTP/metabolismo , Quinases Associadas a rho/metabolismo
5.
Cardiovasc Res ; 113(6): 586-597, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28407046

RESUMO

Aims: Extracellular matrix (ECM) proteins accumulation contributes to the progression of pulmonary arterial hypertension (PAH), a rare and fatal cardiovascular condition defined by high pulmonary arterial pressure, whether primary, idiopathic, or secondary to other causes. The receptor for advanced glycation end products (RAGE) is constitutively expressed in the lungs and plays an important role in ECM deposition. Nonetheless, the mechanisms by which RAGE mediates ECM deposition/formation in pulmonary arteries and its roles in PAH progression remain unclear. Methods and results: Expression of RAGE and its activating ligands, S100/calgranulins and high mobility group box 1 (HMGB1), were increased in both human and mouse pulmonary arterial smooth muscle cells (PASMCs) under hypoxic conditions and were also strikingly upregulated in pulmonary arteries in hypoxia plus SU5416 (HySu)-induced PAH in mice. RAGE deletion alleviated pulmonary arterial pressure and restrained extracellular matrix accumulation in pulmonary arteries in HySu-induced PAH murine model. Moreover, blocking RAGE activity with a neutralizing antibody in human PASMCs, or RAGE deficiency in mouse PASMCs exposed to hypoxia, suppressed the expression of fibrotic proteins by reducing TGF-ß1 expression. RAGE reconstitution in deficient mouse PASMCs restored hypoxia-stimulated TGF-ß1 production via ERK1/2 and p38 MAPK pathway activation and subsequently increased ECM protein expression. Interestingly, HMGB1 acting on RAGE, not toll-like receptor 4 (TLR4), induced ECM deposition in PASMCs. Finally, in both idiopathic PAH patients and HySu-induced PAH mice, soluble RAGE (sRAGE) levels in serum were significantly elevated compared to those in controls. Conclusions: Activation of RAGE facilitates the development of hypoxia-induced pulmonary hypertension by increase of ECM deposition in pulmonary arteries. Our results indicate that sRAGE may be a potential biomarker for PAH diagnosis and disease severity, and that RAGE may be a promising target for PAH treatment.


Assuntos
Proteínas da Matriz Extracelular/metabolismo , Hipertensão Pulmonar/induzido quimicamente , Indóis , Artéria Pulmonar/metabolismo , Pirróis , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Remodelação Vascular , Animais , Estudos de Casos e Controles , Hipóxia Celular , Células Cultivadas , Proteínas do Citoesqueleto/metabolismo , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Humanos , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas com Domínio LIM/metabolismo , Ligantes , Masculino , Pessoa de Meia-Idade , Fosforilação , Artéria Pulmonar/patologia , Interferência de RNA , Receptor para Produtos Finais de Glicação Avançada/genética , Subunidade beta da Proteína Ligante de Cálcio S100/genética , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Transfecção , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
6.
Circ Cardiovasc Genet ; 10(1)2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28077433

RESUMO

BACKGROUND: Pulmonary arterial remodeling characterized by increased vascular smooth muscle proliferation is commonly seen in life-threatening disease, pulmonary arterial hypertension (PAH). Clinical studies have suggested a correlation between osteoprotegerin serum levels and PAH severity. Here, we aimed to invhestigate vascular osteoprotegerin expression and its effects on pulmonary arterial smooth muscle cell proliferation in vitro and in vivo, as well as examine the signal transduction pathways mediating its activity. METHODS AND RESULTS: Serum osteoprotegerin levels were significantly elevated in patients with PAH and correlated with disease severity as determined by the World Health Organization (WHO) functional classifications and 6-minute walking distance tests. Similarly, increased osteoprotegerin expression was observed in the pulmonary arteries of hypoxia plus SU5416- and monocrotaline-induced PAH animal models. Moreover, osteoprotegerin disruption attenuated hypoxia plus SU5416-induced PAH progression by reducing pulmonary vascular remodeling, whereas lentiviral osteoprotegerin reconstitution exacerbated PAH by increasing pulmonary arterial smooth muscle cell proliferation. Furthermore, pathway analysis revealed that osteoprotegerin induced pulmonary arterial smooth muscle cell proliferation by interacting with integrin αvß3 to elicit downstream focal adhesion kinase and AKT pathway activation. CONCLUSIONS: Osteoprotegerin facilitates PAH pathogenesis by regulating pulmonary arterial smooth muscle cell proliferation, suggesting that it may be a potential biomarker and therapeutic target in this disease.


Assuntos
Pressão Arterial , Quinase 1 de Adesão Focal/metabolismo , Hipertensão Pulmonar/prevenção & controle , Hipóxia/complicações , Indóis , Músculo Liso Vascular/enzimologia , Osteoprotegerina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirróis , Transdução de Sinais , Animais , Estudos de Casos e Controles , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Feminino , Quinase 1 de Adesão Focal/genética , Humanos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/enzimologia , Hipertensão Pulmonar/fisiopatologia , Integrina alfaVbeta3/genética , Integrina alfaVbeta3/metabolismo , Masculino , Camundongos Knockout , Pessoa de Meia-Idade , Monocrotalina , Músculo Liso Vascular/fisiopatologia , Osteoprotegerina/sangue , Osteoprotegerina/deficiência , Osteoprotegerina/genética , Artéria Pulmonar/enzimologia , Artéria Pulmonar/fisiopatologia , Interferência de RNA , Ratos Sprague-Dawley , Índice de Gravidade de Doença , Transfecção , Remodelação Vascular , Teste de Caminhada
7.
Pulm Pharmacol Ther ; 33: 39-46, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26086178

RESUMO

Pulmonary hypertension (PH) is a rapidly progressive disease that eventually leads to right heart failure and death. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors (TRAIL-Rs) play an important role in the survival, migration, and proliferation of vascular smooth muscle cells. However, the association between serum TRAIL levels and PH is unknown. In this study, we assayed the serum soluble TRAIL (sTRAIL) levels in 78 patients with PH and 80 controls. The sTRAIL concentrations were elevated in the PH patients compared with the controls (138.76 ± 6.60 pg/mL vs. 80.14 ± 3.38 pg/mL, p < 0.0001). The presence of sTRAIL levels of >103 pg/mL could discriminate PH patients from healthy individuals, with a sensitivity of 75.6% and specificity of 81.2%. Moreover, elevated sTRAIL concentrations were associated with eventual pathological complications; this is consistent with the finding that sTRAIL levels decreased in patients who responded to treatment. In a hypoxia-induced PH mouse model, sTRAIL levels were significantly higher compared with those in normoxia mice, and clearly decreased when the mice were treated with treprostinil. The sTRAIL levels were positively correlated with right ventricular systolic pressure and the index of right ventricular hypertrophy. In conclusion, serum sTRAIL could be a biomarker for diagnosis and effective therapy for PH patients.


Assuntos
Hipertensão Pulmonar/fisiopatologia , Hipóxia/complicações , Ligante Indutor de Apoptose Relacionado a TNF/sangue , Animais , Estudos de Casos e Controles , Modelos Animais de Doenças , Epoprostenol/análogos & derivados , Epoprostenol/farmacologia , Feminino , Humanos , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/tratamento farmacológico , Hipóxia/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Estudos Prospectivos , Sensibilidade e Especificidade , Índice de Gravidade de Doença
8.
J Clin Invest ; 125(3): 1228-42, 2015 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-25664856

RESUMO

Pulmonary arterial hypertension (PAH) is commonly associated with chronic hypoxemia in disorders such as chronic obstructive pulmonary disease (COPD). Prostacyclin analogs are widely used in the management of PAH patients; however, clinical efficacy and long-term tolerability of some prostacyclin analogs may be compromised by concomitant activation of the E-prostanoid 3 (EP3) receptor. Here, we found that EP3 expression is upregulated in pulmonary arterial smooth muscle cells (PASMCs) and human distal pulmonary arteries (PAs) in response to hypoxia. Either pharmacological inhibition of EP3 or Ep3 deletion attenuated both hypoxia and monocrotaline-induced pulmonary hypertension and restrained extracellular matrix accumulation in PAs in rodent models. In a murine PAH model, Ep3 deletion in SMCs, but not endothelial cells, retarded PA medial thickness. Knockdown of EP3α and EP3ß, but not EP3γ, isoforms diminished hypoxia-induced TGF-ß1 activation. Expression of either EP3α or EP3ß in EP3-deficient PASMCs restored TGF-ß1 activation in response to hypoxia. EP3α/ß activation in PASMCs increased RhoA-dependent membrane type 1 extracellular matrix metalloproteinase (MMP) translocation to the cell surface, subsequently activating pro-MMP-2 and promoting TGF-ß1 signaling. Activation or disruption of EP3 did not influence PASMC proliferation. Together, our results indicate that EP3 activation facilitates hypoxia-induced vascular remodeling and pulmonary hypertension in mice and suggest EP3 inhibition as a potential therapeutic strategy for pulmonary hypertension.


Assuntos
Hipertensão Pulmonar/metabolismo , Receptores de Prostaglandina E Subtipo EP3/genética , Fator de Crescimento Transformador beta1/fisiologia , Proteínas rho de Ligação ao GTP/metabolismo , Animais , Hipóxia Celular , Células Cultivadas , Matriz Extracelular/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Hipertensão Pulmonar/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Artéria Pulmonar/metabolismo , Ratos Sprague-Dawley , Receptores de Prostaglandina E Subtipo EP3/antagonistas & inibidores , Receptores de Prostaglandina E Subtipo EP3/metabolismo , Transdução de Sinais , Sulfonamidas/farmacologia , Remodelação Vascular
9.
Blood ; 124(10): 1610-21, 2014 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-25030064

RESUMO

Cyclooxygenases (COXs) and their prostanoid products play important roles in a diverse range of physiological processes, including in the immune system. Here, we provide evidence that COX-1 is an essential regulator in early stages of B-cell development. COX-1-deficient mice displayed systematic reduction in total B cells, which was attributed to the arrest of early B-cell development from pro-B to pre-B stage. We further demonstrated that this defect was mediated through downregulation of the Janus kinase/signal transducer and activator of transcription 5 (JAK/STAT5) signaling and its target genes, including Pax5, in COX-1(-/-) mice. Mechanistic studies revealed that COX-1-derived thromboxane A2 (TxA2) could regulate JAK3/STAT5 signaling through the cyclic adenosine monophosphate-protein kinase A pathway, via binding with its receptor thromboxane A2 receptor (TP). Administration of the TP agonist could rescue the defective B-cell development and JAK/STAT5 signaling activity in COX-1-deficient mice. Moreover, administration of low-dose aspirin caused a significant reduction in total B cells in peripheral blood of healthy human volunteers, coincidentally with reduced TxA2 production and downregulation of JAK/STAT5 signaling. Taken together, our results demonstrate that COX-1-derived TxA2 plays a critical role in the stage transition of early B-cell development through regulation of JAK/STAT5 signaling and indicate a potential immune-suppressive effect of low-dose aspirin in humans.


Assuntos
Linfócitos B/fisiologia , Diferenciação Celular , Ciclo-Oxigenase 1/metabolismo , Proteínas de Membrana/metabolismo , Tromboxano A2/fisiologia , Animais , Diferenciação Celular/genética , Células Cultivadas , Ciclo-Oxigenase 1/genética , Humanos , Janus Quinases/metabolismo , Leucopoese/genética , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais/genética , Tromboxano A2/metabolismo
10.
J Allergy Clin Immunol ; 134(5): 1163-74.e16, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24948368

RESUMO

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) have recently been implicated in the pathogenesis of asthma, but their regulation in patients with aspirin-intolerant asthma (AIA) remains unclear. OBJECTIVE: We sought to characterize MDSC accumulation and pathogenic functions in allergic airway inflammation mediated by COX-1 deficiency or aspirin treatment in mice. METHODS: Allergic airway inflammation was induced in mice by means of ovalbumin challenge. The distribution and function of MDSCs in mice were analyzed by using flow cytometry and pharmacologic/gene manipulation approaches. RESULTS: CD11b(+)Gr1(high)Ly6G(+)Ly6C(int) MDSCs (polymorphonuclear MDSCs [PMN-MDSCs]) recruited to the lungs are negatively correlated with airway inflammation in allergen-challenged mice. Aspirin-treated and COX-1 knockout (KO) mice showed significantly lower accumulation of PMN-MDSCs in the inflamed lung and immune organs accompanied by increased TH2 airway responses. The TH2-suppressive function of PMN-MDSCs was notably impaired by COX-1 deletion or inhibition, predominantly through downregulation of arginase-1. COX-1-derived prostaglandin E2 promoted PMN-MDSC generation in bone marrow through E prostanoid 2 and 4 receptors (EP2 and EP4), whereas the impaired arginase-1 expression in PMN-MDSCs in COX-1 KO mice was mediated by dysregulation of the prostaglandin E2/EP4/cyclic AMP/protein kinase A pathway. EP4 agonist administration alleviated allergy-induced airway hyperresponsiveness in COX-1 KO mice. Moreover, the immunosuppressive function of PMN-MDSCs from patients with AIA was dramatically decreased compared with that from patients with aspirin-tolerant asthma. CONCLUSION: The immunosuppressive activity of PMN-MDSCs was diminished in both allergen-challenged COX-1 KO mice and patients with AIA, probably through an EP4-mediated signaling pathway, indicating that activation of PMN-MDSCs might be a promising therapeutic strategy for asthma, particularly AIA.


Assuntos
Asma Induzida por Aspirina/imunologia , Tolerância Imunológica , Células Mieloides/imunologia , Transdução de Sinais/imunologia , Alérgenos/toxicidade , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/farmacologia , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/imunologia , Arginase/genética , Arginase/imunologia , Aspirina/efeitos adversos , Aspirina/farmacologia , Asma Induzida por Aspirina/genética , Asma Induzida por Aspirina/patologia , Proteínas Quinases Dependentes de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/imunologia , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 1/imunologia , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , Células Mieloides/patologia , Receptores de Prostaglandina E Subtipo EP2/genética , Receptores de Prostaglandina E Subtipo EP2/imunologia , Receptores de Prostaglandina E Subtipo EP4/genética , Receptores de Prostaglandina E Subtipo EP4/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Células Th2/imunologia , Células Th2/patologia
11.
J Biol Chem ; 289(17): 11681-94, 2014 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-24619416

RESUMO

Inadequate vitamin D status has been linked to increased risk of type 2 diabetes and cardiovascular disease. Inducible cyclooxygenase (COX) isoform COX-2 has been involved in the pathogenesis of such chronic inflammatory diseases. We found that the active form of vitamin D, 1,25(OH)2D produces dose-dependent inhibition of COX-2 expression in murine macrophages under both basal and LPS-stimulated conditions and suppresses proinflammatory mediators induced by LPS. Administration of 1,25(OH)2D significantly alleviated local inflammation in a carrageenan-induced paw edema mouse model. Strikingly, the phosphorylation of both Akt and its downstream target IκBα in macrophages were markedly suppressed by 1,25(OH)2D in the presence and absence of LPS stimulation through up-regulation of THEM4 (thioesterase superfamily member 4), an Akt modulator protein. Knockdown of both vitamin D receptor and THEM4 attenuated the inhibitory effect of 1,25(OH)2D on COX-2 expression in macrophages. A functional vitamin D-responsive element in the THEM4 promoter was identified by chromatin immunoprecipitation and luciferase reporter assay. Our results indicate that vitamin D restrains macrophage-mediated inflammatory processes by suppressing the Akt/NF-κB/COX-2 pathway, suggesting that vitamin D supplementation might be utilized for adjunctive therapy for inflammatory disease.


Assuntos
Calcitriol/farmacologia , Ciclo-Oxigenase 2/genética , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Inflamação/prevenção & controle , Tioléster Hidrolases/metabolismo , Animais , Sequência de Bases , Carragenina/toxicidade , Linhagem Celular , Primers do DNA , Ensaio de Imunoadsorção Enzimática , Ácidos Graxos não Esterificados/metabolismo , Humanos , Inflamação/induzido quimicamente , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/enzimologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Prostaglandinas/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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