Proinflammatory Effect of Sodium 4-Phenylbutyrate in ΔF508-Cystic Fibrosis Transmembrane Conductance Regulator Lung Epithelial Cells: Involvement of Extracellular Signal-Regulated Protein Kinase 1/2 and c-Jun-NH2-Terminal Kinase Signaling

Roque, Telma; Boncoeur, Émilie; Saint‐Criq, Vinciane; Bonvin, Elise; Clément, Annick; Tabary, Olivier; Jacquot, Jacky

doi:10.1124/jpet.107.135186

Cited by 25 publications

(23 citation statements)

References 39 publications

(56 reference statements)

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“…Interestingly, earlier studies investigating the effects of butyrate and its derivative 4-phenylbutyrate on pharmacological rescue of F508del-CFTR found, in line with our results, that 4-phenylbutyrate (at 6-10 mM) had a pro-inflammatory effect on CFBE cells (CFBE41o-, also used in this study, and IB3-1 cells) by upregulating IL-8 [25,26]. However, in our study there was no correlation between SCFA concentrations at the time of pulmonary exacerbation with IL-8 or the change in IL-8 after antibiotic treatment, and no correlation between the change in SCFA concentrations before and after antibiotic treatment with either the change in IL-8 or the levels of IL-8 after antibiotic treatment, illustrating that SCFAs may contribute to but are not the major factor affecting individual IL-8 levels.…”

Section: Discussionsupporting

confidence: 79%

“…In contrast, high concentrations markedly abrogated iNOS expression in A549 as well as primary control and cystic fibrosis epithelial cells. While it is not clear whether the effect on iNOS expression was direct or mediated by changes in the inflammatory response, SCFAs and their derivatives have previously been shown to directly inhibit activation of nuclear factor-κB, a key regulator of iNOS transcription [26,36]. The presence of SCFAs in airways may contribute to the dysregulation of NOS in cystic fibrosis airways, which is supported by our observation that lower concentrations of these bacterial metabolites in sputum of cystic fibrosis patients were predictive for the increase in airway NO after antibiotic therapy in our small cohort.…”

Section: Discussionmentioning

confidence: 99%

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Short-chain fatty acids affect cystic fibrosis airway inflammation and bacterial growth

et al. 2015

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The hypoxic environment of cystic fibrosis airways allows the persistence of facultative anaerobic bacteria, which can produce short-chain fatty acids (SCFAs) through fermentation. However, the relevance of SCFAs in cystic fibrosis lung disease is unknown. We show that SCFAs are present in sputum samples from cystic fibrosis patients in millimolar concentrations (mean±SEM 1.99±0.36 mM).SCFAs positively correlated with sputum neutrophil count and higher SCFAs were predictive for impaired nitric oxide production. We studied the effects of the SCFAs acetate, propionate and butyrate on airway inflammatory responses using epithelial cell lines and primary cell cultures. SCFAs in concentrations present in cystic fibrosis airways (0.5-2.5 mM) affected the release of granulocytemacrophage colony-stimulating factor, granulocyte colony-stimulating factor and interleukin (IL)-6. SCFAs also resulted in higher IL-8 release from stimulated cystic fibrosis transmembrane conductance regulator (CFTR) F508del-mutant compared to wild-type CFTR-corrected bronchial epithelial cells. At 25 mM propionate reduced IL-8 release in control but not primary cystic fibrosis epithelial cells. Low (0.5-2.5 mM) SCFA concentrations increased, while high (25-50 mM) concentrations decreased inducible nitric oxide synthase expression. In addition, SCFAs affected the growth of Pseudomonas aeruginosa in a concentration-and pH-dependent manner.Thus, our data suggest that SCFAs contribute to cystic fibrosis-specific alterations of responses to airway infection and inflammation. @ERSpublications Short-chain fatty acids contribute to CF-specific alterations of responses to airway infection and inflammation

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Short-chain fatty acids affect cystic fibrosis airway inflammation and bacterial growth

et al. 2015

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“…The treatment of cells with other inducers of HDACi in vitro (such as trichostatin A) was shown to modulate IL-8 production in both an NFkB-dependent and AP-1-dependent fashion, but this effect is highly cell-specific (33,45). In addition, Roque and colleagues observed that 4-PBA enhances the production of IL-8 in lung epithelial cells expressing DF508-CFTR (44). The treatment of these cystic fibrosis cell lines with 4-PBA resulted in an activation of intracellular JNK signaling and the release of IL-8, despite a decrease in NFkB activation, a result similar to what we observed here in cells expressing BRICHOS mutants (Figures 7, 8, and E4).…”

Section: Discussionmentioning

confidence: 97%

“…Mechanistically, the lack of an antiinflammatory effect of 4-PBA in our model system may have been attributable to off-target effects of 4-PBA, as described in other systems. These effects include histone deactylase inhibition (HDACi) (41)(42)(43) and enhanced MAPK (JNK) signaling (44). The treatment of cells with other inducers of HDACi in vitro (such as trichostatin A) was shown to modulate IL-8 production in both an NFkB-dependent and AP-1-dependent fashion, but this effect is highly cell-specific (33,45).…”

Section: Discussionmentioning

confidence: 99%

Endoplasmic Reticulum Stress Induced by Surfactant Protein C BRICHOS Mutants Promotes Proinflammatory Signaling by Epithelial Cells

Maguire

Mulugeta

Beers

2011

Am J Respir Cell Mol Biol

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Chronic interstitial lung disease in both adults and children is associated with mutations of the surfactant protein C (SP-C) proprotein. Among these, mutations within the distal COOH propeptide, known as the BRICHOS domain, are associated with a severe disease phenotype. We showed that prolonged expression of the BRICHOS mutants, SP-C Dexon4 and SP-C L188Q , destabilizes endoplasmic reticulum (ER) quality-control mechanisms (the unfolded protein response, or UPR), resulting in the induction of ER stress signaling, an inhibition of the ubiquitin/proteasome system, and the activation of apoptotic pathways. Based on recent observations that the UPR and ER stress can be linked to the induction of proinflammatory signaling, we hypothesized that the epithelial cell dysfunction mediated by SP-C BRICHOS mutants would activate proinflammatory signaling pathways. In a test of this hypothesis, A549 and human embryonic kidney epithelial (HEK293) cells, transiently transfected with either SP-C Dexon4 or SP-C L188Q mutants, each promoted the upregulation of multiple UPR response genes, including homocysteine-inducible, endoplasmic reticulum stressinducible, ubiquitin-like domain member 1 (HERPUD1) and GRP78. Commensurate with these results, increases in IL-8 secretion occurred and were accompanied by the activation of c-Jun N-terminal kinase (JNK)/activating protein-1 signaling. The stimulation of IL-8 cytokine release was completely attenuated by treatment with the JNK-specific inhibitor, SP600125. In addition, SP-C Dexon4 , but not SP-C L188Q , activated NFkB. The treatment of SP-C Dexon4 transfected cells with 4-phenylbutyric acid, a small molecule chaperone known to improve protein folding, blocked the activation of NFkB, but not the release of IL-8. Taken together, the results support the role of JNK signaling in mediating SP-C BRICHOS-induced cytokine release, and provide a link between SP-C BRICHOS mutants and proinflammatory cytokine signaling.

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“…The MAPK family of serine-threonine protein kinases is a highly conserved family consisting of three primary members; extracellular signal-related kinases (ERK), c-Jun amino-terminal kinases (JNK), and p38. MAPKs play an active signaling role following multiple stimuli, some of which include irradiation, osmotic stress, inflammation, growth factors, and mechanical loading (8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

VSL#3 probiotics regulate the intestinal epithelial barrier inï¿½vivo and in vitro via the p38 and ERK signaling pathways

Jiang

2011

Int J Mol Med

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Abstract. Probiotics can play a role in enhancing intestinal barrier function. However, the underlying mechanisms are not fully understood. The aim of this study was to examine the effects of VSL#3 probiotics on colonic epithelium permeability, tight junction protein expression and MAPKs signaling pathways in vivo and in vitro. In vivo, acute colitis was induced by administration of 3.5% dextran sodium sulfate for 7 days. Rats in two groups were treated with either 15 mg VSL#3 or placebo via a gastric tube once daily after induction of colitis. Tight junction protein expression and the MAPKs signaling pathways were studied by immunohistochemistry and immunoblotting. In vitro, HT-29 cells were exposed to TNF-α for up to 48 h with or without pre-treatment with a p38 MAPK inhibitor, an ERK inhibitor or a JNK inhibitor. Then tight junction proteins and the phosphorylation of MAPKs were examined in the presence or absence of VSL#3. In vivo, VSL#3 probiotics significantly ameliorated the disease activity index from Day 4 onward. In acute colitis rats, decreased expression of the tight junction proteins were observed, whereas VSL#3 therapy prevented these changes and increased the expression of phosphorylated p38 (P-p38), and of phosphorylated ERK (P-ERK). In vitro, tight junction proteins, P-p38 and P-ERK in the VSL#3 group were significantly higher than in the control and TNF-α groups. The p38 MAPK inhibitor and the ERK inhibitor could effectively prevent this effect. VSL#3 probiotics protected the epithelial barrier and increased the tight junction protein expression in vivo and in vitro by activating the p38 and ERK signaling pathways.

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Proinflammatory Effect of Sodium 4-Phenylbutyrate in ΔF508-Cystic Fibrosis Transmembrane Conductance Regulator Lung Epithelial Cells: Involvement of Extracellular Signal-Regulated Protein Kinase 1/2 and c-Jun-NH2-Terminal Kinase Signaling

Abstract: Sodium

Cited by 25 publications

References 39 publications

Short-chain fatty acids affect cystic fibrosis airway inflammation and bacterial growth

Short-chain fatty acids affect cystic fibrosis airway inflammation and bacterial growth

Endoplasmic Reticulum Stress Induced by Surfactant Protein C BRICHOS Mutants Promotes Proinflammatory Signaling by Epithelial Cells

VSL#3 probiotics regulate the intestinal epithelial barrier inï¿½vivo and in vitro via the p38 and ERK signaling pathways

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