Central Role of Double-Stranded RNA-Activated Protein Kinase in Microbial Induction of Nitric Oxide Synthase

Uetani, Kohsaku; Der, Sandy D.; Zamanian-Daryoush, Maryam; Motte, Carol de la; Lieberman, Belinda Y.; Williams, Bryan R.G.; Erzurum, Serpil C.

doi:10.4049/jimmunol.165.2.988

Cited by 88 publications

(84 citation statements)

References 46 publications

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“…NO is produced by iNOS, whose promoter has STAT-binding elements (Ganster et al, 2001). In agreement with our results, it has been shown that LPS can not induce iNOS in PKR Ϫ/Ϫ MEF and PKR Ϫ/Ϫ bone marrow-derived macrophage (BMDM) (Uetani et al, 2000;Hsu et al, 2004), indicating that PKR has a central role in the general signaling pathway to iNOS. In addition, LPS was observed to induce the production of NO by activating STAT1 (Jacobs and Ignarro, 2001).…”

Section: Discussionsupporting

confidence: 92%

“…PKR has been shown to mediate the activation of important transcription factors such as I B (Kumar et al, 1994;Zamanian-Daryoush et al, 2000), Tat protein encoded by the human immunodeficiency virus (HIV), the 90-kDa NFAT protein, M-phase-specific dsRNA-binding phosphoprotein MPP4, IFN regulatory factor-1 (IRF-1), and activating transcription factor-2 (ATF-2) (Kirchhoff et al, 1995;McMillan et al, 1995;Langland et al, 1999;Patel et al, 1999). These, in turn, regulate the expression of proinflammatory genes, including inducible nitric oxide synthase (iNOS), interleukin-1 (IL-1), and IL-6 (Uetani et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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Double-stranded RNA-activated protein kinase is required for the LPS-induced activation of STAT1 inflammatory signaling in rat brain glial cells

Lee

Park

Kim

et al. 2005

Glia

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PKR, the double-stranded RNA (dsRNA)-activated serine/threonine kinase, has been implicated as an important component of host responses to infection and various situations of cellular stress. The involvement of PKR in signal transduction and regulation of transcription suggested to us that it may play an important role in lipopolysaccharide (LPS)-induced activation of STAT1 in rat brain immune cells. We found that LPS rapidly stimulated the phosphorylation of PKR within 5 min, followed by phosphorylation of STAT1 at 2 h in rat primary microglia and astrocyte. Using 2-aminopurine (2-AP), a pharmacological inhibitor of PKR, and PKR-specific short interfering RNA (siRNA), we demonstrated that activation of PKR was essential for LPS-induced activation of STAT1. Inhibition of PKR activity by 2-AP resulted in suppression not only of STAT1 phosphorylation, but also of nuclear factors binding activity to GAS/ISRE elements. 2-AP also significantly suppressed the downstream events of LPS-stimulated STAT1 phosphorylation, including STAT-mediated transcriptional responses and generation of nitric oxide, a hallmark of brain inflammation. Consistent with these results, transfection of PKR-specific siRNA markedly attenuated all the STAT1 dependent inflammatory signaling responses tested. We further revealed that activation of PKR by LPS led to the induction of IFN-␤ through activation of NF-B, triggering the phosphorylation of STAT1 in rat brain glial cells. Taken together, these findings indicate that PKR functions as an essential modulator in LPS-induced STAT inflammatory signaling events, and provides new insight into endotoxin-induced CNS diseases following infection.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Double-stranded RNA-activated protein kinase is required for the LPS-induced activation of STAT1 inflammatory signaling in rat brain glial cells

Lee

Park

Kim

et al. 2005

Glia

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“…Beas2B cells were obtained from ATCC and cultured using LHC9 medium (Lonza). Normal human primary bronchial epithelial cells (NHBE) were obtained by bronchoscopy and airway brushing of normal, nonsmoking volunteers with no history of lung disease or current medications (30,31), or from surgical specimens of tracheas and mainstem bronchi, as previously described (31). All human tissue was acquired under protocols approved by the National Jewish Health Institutional Review Board.…”

Section: Methodsmentioning

confidence: 99%

Pulmonary surfactant phosphatidylglycerol inhibits respiratory syncytial virus–induced inflammation and infection

Numata

Chu

Dakhama

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

155

244

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Respiratory syncytial virus (RSV) is the most common cause of hospitalization for respiratory tract infection in young children. It is also a significant cause of morbidity and mortality in elderly individuals and in persons with asthma and chronic obstructive pulmonary disease. Currently, no reliable vaccine or simple RSV antiviral therapy is available. Recently, we determined that the minor pulmonary surfactant phospholipid, palmitoyl-oleoyl-phosphatidylglycerol (POPG), could markedly attenuate inflammatory responses induced by lipopolysaccharide through direct interactions with the Toll-like receptor 4 (TLR4) interacting proteins CD14 and MD-2. CD14 and TLR4 have been implicated in the host response to RSV. Treatment of bronchial epithelial cells with POPG significantly inhibited interleukin-6 and -8 production, as well as the cytopathic effects induced by RSV. The phospholipid bound RSV with high affinity and inhibited viral attachment to HEp2 cells. POPG blocked viral plaque formation in vitro by 4 log units, and markedly suppressed the expansion of plaques from cells preinfected with the virus. Administration of POPG to mice, concomitant with viral infection, almost completely eliminated the recovery of virus from the lungs at 3 and 5 days after infection, and abrogated IFN-γ (IFN-γ) production and the enhanced expression of surfactant protein D (SP-D). These findings demonstrate an important approach to prevention and treatment of RSV infections using exogenous administration of a specific surfactant phospholipid.antiviral | innate immunity | respiratory epithelium R espiratory syncytial virus (RSV) is an important pathogen that infects 98% of children within the first 2 years of life, and also causes serious disease in elderly individuals and persons with chronic lung disease. In the 1980s, an estimated 100,000 children were hospitalized annually with RSV infection in the United States (1). Although RSV is commonly considered a pediatric disease, it is also highlighted as an opportunistic pathogen (2), with infections producing a mortality rate of 30-100% in immunosuppressed individuals (1). There is growing appreciation that RSV is an important pathogen in elderly and high-risk patients, and a cause of acute exacerbations of asthma (3, 4) and chronic obstructive pulmonary disease (COPD) (5). Over the period 1999-2003, RSV was responsible for hospitalization rates of 10.6% for pneumonia, 11.4% for COPD, 5.4% for congestive heart failure, and 7.2% for asthma (6).No vaccine is currently available for prevention of RSV infection. Several vaccine candidates have not only proved to be ineffective, but have also been shown to lead to vaccine-enhanced disease (7,8). Inhibitors directed against the RSV fusion protein (F protein) were abandoned partly because of the frequency of resistant mutations mapping to the F gene (9). A monoclonal antibody against F protein, Palivizumab, has restricted application and it is recommended for prophylactic use during the RSV season, for high-risk infants (1). Currently the onl...

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“…Other genes that are activated during IFN-c-dependent immunity include ICAM-1, for leukocyte recruitment and activation [42], and IRF-1, a transcription factor that amplifies the antiviral response [7,8,43]. Human GBP1 has been shown to exhibit antiviral activity against vesicular stomatitis virus and encephalomyocarditis virus [44].…”

Section: Influenza a Virus Inhibits Ifn-c-stimulated Icam-1 Irf-1 Imentioning

confidence: 99%

“…The first site of viral contact with the host and main target of infection and inflammation is the airway mucosal epithelium. Epithelial cells at the airway mucosal surface have a variety of inflammatory and immune defense mechanisms to deal with virus, including expression of cytokines with chemoattractant and proinflammatory functions [5], intercellular adhesion molecule-1 (ICAM-1) [6], IFN regulatory factor 1 (IRF-1) [7], nitric oxide synthase 2 (NOS2) [8], and MHC class II [9]. IFN-c, one of the key regulatory cytokines in the host immune response against viral infections, is secreted by T lymphocytes and natural killer (NK) cells.…”

Section: Introductionmentioning

confidence: 99%

Influenza A virus abrogates IFN‐γ response in respiratory epithelial cells by disruption of the Jak/Stat pathway

et al. 2008

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The innate immunity to viral infections induces a potent antiviral response mediated by interferons (IFN). Although IFN-c is detected during the acute stages of illness in the upper respiratory tract secretions and in the serum of influenza A virus-infected individuals, control of influenza A virus is not dependent upon IFN-c as evidenced by studies using anti-IFN-c Ab and IFN-c -/-mice. Thus, we hypothesized that IFN-c is not critical in host survival because influenza A virus has mechanisms to evade the antiviral activity of IFN-c. To test this, A549 cells, an epithelial cell line derived from lung adenocarcinoma, were infected with influenza virus strain A/Aichi/2/68 (H3N2) (Aichi) and/or stimulated with IFN-c to detect IFN-c-stimulated MHC class II expression. Influenza A virus infection inhibited IFN-c-induced up-regulation of HLA-DRa mRNA and the IFN-c induction of class II transactivator (CIITA), an obligate mediator of MHC class II expression. Nuclear translocation of Stat1a upon IFN-c stimulation was significantly inhibited in influenza A virus-infected cells and this was associated with a decrease in Tyr701 and Ser727 phosphorylation of Stat1a. Thus, influenza A virus subverts antiviral host defense mediated by IFN-c through effects on the intracellular signaling pathways. IntroductionInfluenza A viruses are negative-strand RNA viruses that have a segmented genome with a coding capacity for 11 polypeptides. The virus genome is composed of eight different RNA segments, which are tightly associated with the viral nucleoprotein and polymerases in ribonucleoprotein complexes [1]. Influenza A viruses, causing acute infections, continuously escape from recognition by virus neutralizing Ab as a result of accumulation of mutations in their surface glycoproteins hemagglutinin and neuraminidase (antigenic drift) or by introduction of new subtypes of these glycoproteins (antigenic shift) [2,3]. Recent outbreaks of highly pathogenic avian influenza A virus infections in poultry and in humans have raised concerns that a new influenza pandemic will occur in the near future [4]. Thus, prediction of the severity of continuously emerging human influenza virus strains remains a high public health priority, but it is limited by our incomplete understanding of the molecular determinants of pathogenicity in this disease. Although factors dictating the severity of virus disease are complex, interaction between inherent viral properties and host cellular response ultimately determines disease outcome. The first site of viral contact with the host and main target of infection and inflammation is the airway mucosal epithelium. Epithelial cells at the airway mucosal surface have a variety of inflammatory and immune defense mechanisms to deal with virus, including Eur. J. Immunol. 2008. 38: 1559-1573 Immunity to infection expression of cytokines with chemoattractant and proinflammatory functions [5], intercellular adhesion molecule-1 (ICAM-1) [6], IFN regulatory factor 1 (IRF-1) [7], nitric oxide synthase 2 (NOS2) [8], and MHC ...

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Central Role of Double-Stranded RNA-Activated Protein Kinase in Microbial Induction of Nitric Oxide Synthase

Cited by 88 publications

References 46 publications

Double-stranded RNA-activated protein kinase is required for the LPS-induced activation of STAT1 inflammatory signaling in rat brain glial cells

Double-stranded RNA-activated protein kinase is required for the LPS-induced activation of STAT1 inflammatory signaling in rat brain glial cells

Pulmonary surfactant phosphatidylglycerol inhibits respiratory syncytial virus–induced inflammation and infection

Influenza A virus abrogates IFN‐γ response in respiratory epithelial cells by disruption of the Jak/Stat pathway

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