Proinflammatory cytokine responses to<i>P. aeruginosa</i>infection in human airway epithelial cell lines

Kube, Dianne; Sontich, Ute; Fletcher, David; Davis, Pamela B.

doi:10.1152/ajplung.2001.280.3.l493

Cited by 165 publications

(172 citation statements)

References 32 publications

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“…IL-6 is a multipotent cytokine produced in the context of inflammation and infection and is critical to the development of the acute phase response during inflammation (57)(58)(59). We chose to examine the regulation of IL-6 production by mast cells in view of the wide range of biologic activities of IL-6 which are relevant to the initiation and progression of inflammation (59) and because production of IL-6 in the airway has been implicated in P. aeruginosa-associated cystic fibrosis (1,60,61). The mast cell is a potent source of IL-6 and is able to produce this cytokine relatively rapidly compared with the more traditional sources of this cytokine, such as monocytes and macrophages (50,57).…”

Section: Discussionmentioning

confidence: 99%

Protein Phosphatase 2A and Protein Kinase Cα Are Physically Associated and Are Involved in Pseudomonas aeruginosa-induced Interleukin 6 Production by Mast Cells

Boudreau¹,

Garduño²,

Lin³

2002

Journal of Biological Chemistry

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Pulmonary infection with Pseudomonas aeruginosa is characterized by massive airway inflammation, which comprises significant cytokine production. Although mast cells are abundant in the lung and are potent sources of various cytokines, a role of mast cells in P. aeruginosa infection remains undefined, and P. aeruginosa-induced signaling mechanisms in mast cells have not been studied previously. Here we demonstrate that human cord blood-derived mast cells, mouse bone marrow-derived mast cells, and the mouse mast cell line MC/9 produce significant amounts of interleukin 6 (IL-6) in response to P. aeruginosa. This response was accompanied by a stimulation of protein kinase C␣ (PKC␣) phosphorylation and PKC activity and was significantly blocked by the PKC inhibitors Ro 31-8220 and PKC␣ pseudosubstrate. Interestingly, mast cells treated with P. aeruginosa had reduced protein levels of phosphatase 2A catalytic unit (PP2Ac), which prompted us to determine whether a direct association between PKC␣ and PP2A occurs in mast cells. In mouse bone marrowderived mast cells and MC/9 cells, as well as in the human mast cell line HMC-1, PP2A coimmunoprecipitated with PKC␣ either using PKC␣-or PP2Ac-specific antibodies, suggesting that PKC␣ and PP2Ac are physically associated in mast cells. The PP2A inhibitor okadaic acid induced P. aeruginosa-like responses in mast cells including increased PKC␣ phosphorylation, stimulated PKC activity, and augmented IL-6 production, the last being blocked by the PKC inhibitor Ro 31-8220. Finally, okadaic acid potentiated the P. aeruginosa-induced IL-6 production. Collectively, these data provide, to our knowledge, the first evidence of both a direct physical association of PP2A and PKC␣ in mammalian cells and their coinvolvement in regulating mast cell activation in response to P. aeruginosa.

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Section: Discussionmentioning

confidence: 99%

Protein Phosphatase 2A and Protein Kinase Cα Are Physically Associated and Are Involved in Pseudomonas aeruginosa-induced Interleukin 6 Production by Mast Cells

Boudreau¹,

Garduño²,

Lin³

2002

Journal of Biological Chemistry

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“…This inflammatory state is further amplified by bacterial infections, in particular, Pseudomonas aeruginosa (6,7). The presence of bacteria promotes the airway epithelium to release proinflammatory cytokines such as the potent neutrophil chemoattractant IL-8 (8). This sustained inflammatory response recruits neutrophils in an attempt to resolve bacterial infection, yet paradoxically, chronic neutrophil stimulation also leads to neutrophil necrosis (9).…”

mentioning

confidence: 99%

Dysregulation of TIM-3–Galectin-9 Pathway in the Cystic Fibrosis Airways

Vega-Carrascal

Reeves

Niki

et al. 2011

The Journal of Immunology

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The T-cell Ig and mucin domain-containing molecules (TIMs) have emerged as promising therapeutic targets to correct abnormal immune function in several autoimmune and chronic inflammatory conditions. It has been reported that proinflammatory cytokine dysregulation and neutrophil-dominated inflammation are the main causes of morbidity in cystic fibrosis (CF). However, the role of TIM receptors in CF has not been investigated. In this study, we demonstrated that TIM-3 is constitutively overexpressed in the human CF airway, suggesting a link between CF transmembrane conductance regulator (CFTR) function and TIM-3 expression. Blockade of CFTR function with the CFTR inhibitor-172 induced an upregulation of TIM-3 and its ligand galectin-9 in normal bronchial epithelial cells. We also established that TIM-3 serves as a functional receptor in bronchial epithelial cells, and physiologically relevant concentrations of galectin-9 induced TIM-3 phosphorylation, resulting in increased IL-8 production. In addition, we have demonstrated that both TIM-3 and galectin-9 undergo rapid proteolytic degradation in the CF lung, primarily because of neutrophil elastase and proteinase-3 activity. Our results suggest a novel intrinsic defect that may contribute to the neutrophil-dominated immune response in the CF airways.

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“…1 CF is characterized by the dysfunction of the CF transmembrane regulator chloride channel and by abnormal inflammatory signaling, 2,3 excessive inflammatory responses, 4 and impairment in the resolution of inflammation, 5,6 leading to diminishing lung function and increased mortality. Infections with respiratory viruses (eg, influenza and rhinoviruses) are associated with exacerbation of pulmonary problems, disease progression, and increase in bacterial adherence in CF airways, which predisposes to secondary bacterial infection.…”

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confidence: 99%

Safety of Live-Attenuated Influenza Vaccination in Cystic Fibrosis

et al. 2014

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OBJECTIVES: Given the improved efficacy of the nasal live-attenuated influenza virus vaccine (LAIV) compared with the injectable vaccine in children, we aimed to determine its safety in individuals with cystic fibrosis (CF). METHODS: A cohort of 168 study participants, aged 2 to 18 years with CF, vaccinated with LAIV between October 1, 2012, and January 30, 2013, was followed prospectively for 56 days after initial vaccination in 3 pediatric CF clinics across the province of Quebec. Days 0 to 28 post-LAIV were considered the at-risk period for all outcomes of interest, and days 29 to 56 post-LAIV were considered the non–at-risk period. Incident respiratory deteriorations were defined as an unscheduled medical visit, hospitalization, or a new course of oral antibiotics for respiratory complaints. Using a self-controlled design, incidence rate ratios (IRR) were used to compare at-risk and non–at-risk periods. RESULTS: Comparing at-risk to non–at-risk periods, there was no significant increase in the rate of incident respiratory deteriorations (IRR, 0.72; 95% confidence interval, 0.11–4.27) or all-cause hospitalizations (IRR, 1.16; 95% confidence interval, 0.30–4.81). A greater proportion of participants reported experiencing at least 1 minor respiratory and/or systemic adverse event after immunization during the at-risk period compared with the non–at-risk period (77% vs 54%, respectively). During the first week after LAIV, 13 of 168 (8%) children reported some wheezing, with the vast majority, 9 of 13 (69%), on the day of vaccination. CONCLUSIONS: There was no increased risk of respiratory deterioration or all-cause hospitalization associated with LAIV in our study population. LAIV seems well tolerated in children and adolescents with CF.

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Proinflammatory cytokine responses toP. aeruginosainfection in human airway epithelial cell lines

Cited by 165 publications

References 32 publications

Protein Phosphatase 2A and Protein Kinase Cα Are Physically Associated and Are Involved in Pseudomonas aeruginosa-induced Interleukin 6 Production by Mast Cells

Protein Phosphatase 2A and Protein Kinase Cα Are Physically Associated and Are Involved in Pseudomonas aeruginosa-induced Interleukin 6 Production by Mast Cells

Dysregulation of TIM-3–Galectin-9 Pathway in the Cystic Fibrosis Airways

Safety of Live-Attenuated Influenza Vaccination in Cystic Fibrosis

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