Role of p38 Mitogen-Activated Protein Kinase in Rhinovirus-Induced Cytokine Production by Bronchial Epithelial Cells

Griego, Sandra D.; Weston, Cynthia; Adams, Jerry L.; Tal‐Singer, Ruth; Dillon, Susan B.

doi:10.4049/jimmunol.165.9.5211

Cited by 135 publications

(129 citation statements)

References 41 publications

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“…To confirm these observations and to elucidate the impact of cell signaling on cytokine synthesis in our model, cell signaling inhibition experiments have been performed using MAPK inhibitors PD98059, wortmannin, and SB-239063 (15). From these experiments, we learned that particularly PI3K plays a role in the transduction pathway triggered by S. aureus hemB mutants and trypsin for gene transcription of IL-8.…”

Section: Discussionmentioning

confidence: 81%

“…MAPKs were inhibited by pretreatment with either PD98059 (Calbiochem) at a concentration of 50 M and wortmannin (Calbiochem) at a concentration of 100 nM or the selective p38 inhibitor SB-239063 (trans-1-(4 hydroxycyclohexyl)-4-(fluorophenyl)-5-(2-methoxy-pyrimidin-4-yl) imidazole) at a concentration of 30 M, 30 min before challenge with bacterial supernatants (BioSource International) (15).…”

Section: Stimulation Experimentsmentioning

confidence: 99%

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Immunomodulation of Nasal Epithelial Cells by Staphylococcus aureus-Derived Serine Proteases

Rudack

Sachse²,

Albert³

et al. 2009

The Journal of Immunology

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The impact of Staphylococcus aureus in the pathogenesis of chronic rhinosinusitis is not well understood. Therefore, we investigated primary human nasal epithelial cell cultures for their ability to produce IL-8, growth-related oncogene-α, and IL-6 via stimulation with trypsin and culture supernatants of different S. aureus strains and phenotypes. Inhibition of cytokine synthesis was performed using a glucocorticoid, a serine protease inhibitor, and a cysteine protease inhibitor. Finally, signal transduction pathways were analyzed by quantifying phosphorylated forms of MAPKs (PI3K, ERK, and p38) and DNA-binding assays that quantified NF-κB and its inhibition using BAY11-7085. In vitro studies showed that the induction of IL-8, growth-related oncogene-α, and IL-6 by S. aureus culture supernatants was significantly inhibited by the serine protease inhibitor. In contrast, steroids and the cysteine protease inhibitor had little effect. Activation of NF-κB was observed after cell treatment with trypsin and bacterial supernatants, and was inhibited by BAY11-7085 and the serine protease inhibitor. S. aureus serine proteases were identified to modulate chemokine synthesis and activate NF-κB in nasal epithelial cells, and may therefore be relevant for the pathophysiology of chronic rhinosinusitis.

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Section: Discussionmentioning

confidence: 81%

Section: Stimulation Experimentsmentioning

confidence: 99%

Immunomodulation of Nasal Epithelial Cells by Staphylococcus aureus-Derived Serine Proteases

Rudack

Sachse²,

Albert³

et al. 2009

The Journal of Immunology

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“…Treatment with p38 kinase inhibitor (SB203580) shows a suppressed production of inflammatory mediators such as TNF, IL-1, IL-6, CXCL8/IL-8, and GM-CSF (14). p38 kinase is essential for virus-induced cytokine production by bronchial epithelial cells including IL-6, IL-8, and GM-CSF (15)(16)(17). We have shown that p38 kinase is involved in the hyperinduction of TNF-␣ expression in H5N1-infected macrophages (18), although the mechanisms underlying this hyperinduction of cytokine by H5N1 influenza virus have not been elucidated.…”

Section: Induction Of Proinflammatory Cytokines In Primary Humanmentioning

confidence: 99%

Induction of Proinflammatory Cytokines in Primary Human Macrophages by Influenza A Virus (H5N1) Is Selectively Regulated by IFN Regulatory Factor 3 and p38 MAPK

Hui

Lee

Cheung

et al. 2009

The Journal of Immunology

134

116

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The hyperinduction of proinflammatory cytokines and chemokines such as TNF-α, IFN-β, and CCL2/MCP-1 in primary human macrophages and respiratory epithelial cells by the highly pathogenic avian influenza H5N1 is believed to contribute to the unusual severity of human H5N1 disease. Here we show that TNF-α, IFN-β, and IFN-λ1 are the key mediators directly induced by the H5N1 virus in primary human macrophages. In comparison with human influenza (H1N1), the H5N1 virus more strongly activated IFN regulatory factor 3 (IRF3). IRF3 knockdown and p38 kinase inhibition separately and in combination led to a substantial reduction of IFN-β, IFN-λ1, and MCP-1 but only to a partial reduction of TNF-α. IRF3 translocation was independent of p38 kinase activity, indicating that IRF3 and p38 kinase are distinct pathways leading to cytokine production by H5N1 virus. We conclude that IRF3 and p38 kinase separately and predominantly contribute to H5N1-mediated induction of IFN-β, IFN-λ1, and MCP-1 but only partly control TNF-α induction. A more precise identification of the differences in the regulation of TNF-α and IFN-β could provide novel targets for the design of therapeutic strategies for severe human H5N1 influenza and also for treating other causes of acute respiratory distress syndrome.

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“…Rhinovirus infection of the bronchial epithelium induces expression of numerous proinflammatory genes (55)(56)(57)(58). Induction of nuclear factor (NF)-kB and other transcription factors has been clearly demonstrated with several viruses including HRV, RSV, and influenza (59)(60)(61)(62)(63)(64).…”

Section: Virusesmentioning

confidence: 99%

Pathogen-directed Therapy in Acute Exacerbations of Chronic Obstructive Pulmonary Disease

Martínez

2007

Proceedings of the American Thoracic Society

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Acute exacerbations of chronic obstructive pulmonary disease (COPD) are important events in the natural history of this chronic lung disorder. These events can be caused by a large number of infectious and noninfectious agents and are associated with an increased local and systemic inflammatory response. Their frequency and severity have been linked to progressive deterioration in lung function and health status. Infectious pathogens ranging from viral to atypical and typical bacteria have been implicated in the majority of episodes. Most therapeutic regimens to date have emphasized broad, nonspecific approaches to bronchoconstriction and pulmonary inflammation. Increasingly, therapy that targets specific etiologic pathogens has been advocated. These include clinical and laboratory-based methods to identify bacterial infections. Further additional investigation has suggested specific pathogens within this broad class. As specific antiviral therapies become available, better diagnostic approaches to identify specific pathogens will be required. Furthermore, prophylactic therapy for at-risk individuals during high-risk times may become a standard therapeutic approach. As such, the future will likely include aggressive diagnostic algorithms based on the combination of clinical syndromes and rapid laboratory modalities to identify specific causative bacteria or viruses.

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Role of p38 Mitogen-Activated Protein Kinase in Rhinovirus-Induced Cytokine Production by Bronchial Epithelial Cells

Cited by 135 publications

References 41 publications

Immunomodulation of Nasal Epithelial Cells by Staphylococcus aureus-Derived Serine Proteases

Immunomodulation of Nasal Epithelial Cells by Staphylococcus aureus-Derived Serine Proteases

Induction of Proinflammatory Cytokines in Primary Human Macrophages by Influenza A Virus (H5N1) Is Selectively Regulated by IFN Regulatory Factor 3 and p38 MAPK

Pathogen-directed Therapy in Acute Exacerbations of Chronic Obstructive Pulmonary Disease

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