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2.
Biochem Biophys Res Commun ; 494(1-2): 242-248, 2017 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-29032197

RESUMO

Double-stranded RNA derived from viruses induces host immune responses. PD-L1, also known as B7-H1, is an immune-checkpoint molecule associated with the escape of viruses from host immune systems, which plays a role in the persistence of viral infection, resulting in exacerbations of underlying diseases such as asthma and chronic obstructive pulmonary disease. Interleukin (IL)-22 is produced from various immune cells and has protective properties on mucosal tissue. The binding of IL-22 to IL-22 receptor induces STAT3 activation. We investigated the effect of IL-22 on the expression in airway epithelial cells in vitro and in mouse lungs in vivo after the stimulation with an analog of viral double-stranded RNA, polyinosinic-polycytidylic acid (poly I:C). Stimulation with poly I:C upregulated PD-L1 expression on BEAS-2B cells. This upregulation of PD-L1 was attenuated by IL-22 administration. STAT3 phosphorylation was induced by IL-22 and poly I:C. Treatment of cells with STAT3 siRNA abolished the effect of IL-22 on the poly I:C-induced upregulation of PD-L1. This upregulation of PD-L1 was also attenuated by IL-11, a cytokine inducing STAT3 phosphorylation, in BEAS-2B cells. In mouse lung cells in vivo, IL-22 suppressed poly I:C-induced upregulation of PD-L1. These results suggest that IL-22 attenuates virus-induced upregulation of PD-L1 in airway epithelial cells via a STAT3-dependent mechanism.


Assuntos
Antígeno B7-H1/metabolismo , Interleucinas/metabolismo , RNA Viral/imunologia , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Linhagem Celular , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Técnicas de Silenciamento de Genes , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Poli I-C/imunologia , Receptores de Interleucina/metabolismo , Mucosa Respiratória/virologia , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Regulação para Cima , Interleucina 22
3.
Respir Investig ; 53(1): 22-9, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25542600

RESUMO

BACKGROUND: Elucidating the prevalence of asthma and chronic obstructive pulmonary disease (COPD) is important for designing a public health strategy. Recent studies have discriminated a phenotype of COPD with variable airflow limitation (COPD-VAL) associated with asthma-COPD overlap syndrome. Its prevalence remains uncertain. The age and occupational distributions in the town of Hisayama and in Japan are nearly identical. Each disease's prevalence was estimated for the town's residents. METHODS: In 2008, town residents (≥ 40 years) were solicited to participate in a health checkup. Individuals with abnormal spirometry (forced expiratory volume in 1s/forced vital capacity [FEV1/FVC]<70% and/or %FVC<80%) were recommended for further evaluations. Two pulmonologists in a blinded fashion reviewed their medical records, including bronchodilator reversibility. Individuals with airflow limitation were classified as having asthma, COPD, COPD-VAL, or other diseases. The prevalence of each disease was then estimated. RESULTS: A total of 2100 residents (43.4% of residents in the age group) completed spirometry. In 455 residents with abnormal spirometry, 190 residents had further evaluations, and the medical records of 174 residents were reviewed. The prevalence of asthma with airflow limitation, COPD, and COPD-VAL, were 2.0%, 8.4%, and 0.9%, respectively. The prevalence of COPD and COPD-VAL were higher in men and smokers than in women and never-smokers. The prevalence of COPD, but not COPD-VAL or asthma, increased with age. CONCLUSION: The prevalence of asthma with airflow limitation, COPD, and COPD-VAL were estimated in a population of residents (≥ 40 years) in Hisayama.


Assuntos
Asma/epidemiologia , Asma/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Ventilação Pulmonar , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Asma/complicações , Feminino , Volume Expiratório Forçado , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Doença Pulmonar Obstrutiva Crônica/complicações , Fatores Sexuais , Fumar/efeitos adversos , Fumar/epidemiologia , Espirometria , Capacidade Vital
4.
Int Immunol ; 25(11): 643-50, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23988617

RESUMO

Efferocytosis, which is the homeostatic phagocytosis of apoptotic cells, prevents the release of toxic intracellular contents and subsequent tissue damage. Impairment of efferocytosis was reported in alveolar macrophages (AMs) of patients with chronic obstructive pulmonary disease (COPD), a common disease caused by smoking. In COPD, histone deacetylase (HDAC) activity is reduced in AMs. We investigated whether the reduction of HDAC activity is associated with the impairment of efferocytosis. Murine AMs were collected by bronchoalveolar lavage and their ability to efferocytose apoptotic human polymorphonuclear leukocytes was assessed. Pre-treatment of AMs with cigarette smoke extract (CSE) or trichostatin A (TSA), an HDAC inhibitor, suppressed efferocytosis and CSE reduced HDAC activity. TSA inhibited the activity of Rac, a key mediator of efferocytosis. These TSA-induced impairments were restored by treatment of AMs with aminophylline, a potent activator of HDAC. To further elucidate the underlying mechanism, we explored a role of CD9 in TSA-induced impairment of efferocytosis. CD9 is a transmembrane protein of the tetraspanin family that facilitates the uptake of several pathogens and other material. TSA profoundly down-regulated the expression of CD9 on AMs. The expression of CD9 was partly down-regulated by the Rac inhibitor. Pretreatment with an anti-CD9 mAb or CD9 small interfering RNA inhibited efferocytosis, which was attributable to the reduced binding of AMs to apoptotic cells. These results suggest that smoking impairs efferocytosis via inhibition of HDAC/Rac/CD9 pathways. Aminophylline/theophylline is effective in restoring the impairment of efferocytosis and might have benefit for the treatment of patients with COPD.


Assuntos
Apoptose/imunologia , Histona Desacetilases/metabolismo , Macrófagos Alveolares/patologia , Neutrófilos/citologia , Fagocitose/imunologia , Fumar/efeitos adversos , Tetraspanina 29/antagonistas & inibidores , Proteínas rac de Ligação ao GTP/antagonistas & inibidores , Animais , Voluntários Saudáveis , Histona Desacetilases/imunologia , Humanos , Macrófagos Alveolares/enzimologia , Macrófagos Alveolares/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/enzimologia , Neutrófilos/imunologia , Fumar/imunologia , Tetraspanina 29/imunologia , Tetraspanina 29/metabolismo , Proteínas rac de Ligação ao GTP/imunologia , Proteínas rac de Ligação ao GTP/metabolismo
5.
Biochem Biophys Res Commun ; 435(2): 195-201, 2013 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-23660190

RESUMO

Airway viral infection disturbs the health-related quality of life. B7-H1 (also known as PD-L1) is a coinhibitory molecule associated with the escape of viruses from the mucosal immunity, leading to persistent infection. Most respiratory viruses generate double-stranded (ds) RNA during replication. The stimulation of cultured airway epithelial cells with an analog of viral dsRNA, polyinosinic-polycytidylic acid (poly IC) upregulates the expression of B7-H1 via activation of the nuclear factor κB(NF-κB). The mechanism of upregulation was investigated in association with phosphatidylinositol 3-kinases (PI3Ks). Poly IC-induced upregulation of B7-H1 was profoundly suppressed by a pan-PI3K inhibitor and partially by an inhibitor or a small interfering (si)RNA for PI3Kδ in BEAS-2B cells. Similar results were observed in the respiratory syncytial virus-infected cells. The expression of p110δ was detected by Western blot and suppressed by pretreatment with PI3Kδ siRNA. The activation of PI3Kδ is typically induced by oxidative stress. The generation of reactive oxygen species was increased by poly IC. Poly IC-induced upregulation of B7-H1 was attenuated by N-acetyl-L-cysteine, an antioxidant, or by oxypurinol, an inhibitor of xanthine oxidase. Poly IC-induced activation of NF-κB was suppressed by a pan-PI3K inhibitor but not by a PI3Kδ inhibitor. These results suggest that PI3Kδ mediates dsRNA-induced upregulation of B7-H1 without affecting the activation of NF-κB.


Assuntos
Antígeno B7-H1/biossíntese , DNA Viral/metabolismo , Células Epiteliais/citologia , Células Epiteliais/metabolismo , RNA de Cadeia Dupla/metabolismo , Mucosa Respiratória/citologia , Mucosa Respiratória/metabolismo , Linhagem Celular , DNA Viral/administração & dosagem , DNA Viral/genética , Humanos , RNA de Cadeia Dupla/administração & dosagem , RNA de Cadeia Dupla/genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
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