Surfactant lipids regulate LPS-induced interleukin-8 production in A549 lung epithelial cells by inhibiting translocation of TLR4 into lipid raft domains

Abate, Wondwossen; Alghaithy, Abdulaziz A.; Parton, Joan; Jones, Karen; Jackson, Simon K.

doi:10.1194/jlr.m000513

Cited by 69 publications

(55 citation statements)

References 67 publications

(82 reference statements)

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“…It was recently shown that LPS treatment induced activation of TLR4 via its translocation into membrane lipid raft microdomains, and this translocation was inhibited by incubation of the cells with the surfactant lipid. Lipid-mediated inhibition of TLR4 membrane repartition can downregulate the synthesis of IL-8 by an alveolar epithelial cell line in response to LPS (1,49). This recent finding gives rise to the hypothesis that D2S membrane activity may result in rearrangement of lipid packing after D2S membrane insertion, which will interfere with TLR membrane repartition.…”

Section: Discussionmentioning

confidence: 94%

Combined Antibacterial and Anti-Inflammatory Activity of a Cationic Disubstituted Dexamethasone-Spermine Conjugate

Bucki

Leszczyńska²,

Byfield

et al. 2010

Antimicrob Agents Chemother

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The rising number of antibiotic-resistant bacterial strains represents an emerging health problem that has motivated efforts to develop new antibacterial agents. Endogenous cationic antibacterial peptides (CAPs) that are produced in tissues exposed to the external environment are one model for the design of novel antibacterial compounds. Here, we report evidence that disubstituted dexamethasone-spermine (D2S), a cationic corticosteroid derivative initially identified as a by-product of synthesis of dexamethasone-spermine (

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Section: Discussionmentioning

confidence: 94%

Combined Antibacterial and Anti-Inflammatory Activity of a Cationic Disubstituted Dexamethasone-Spermine Conjugate

Bucki

Leszczyńska²,

Byfield

et al. 2010

Antimicrob Agents Chemother

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“…In the current study, phospholipid vesicles comprised of the surfactant phospholipids dipalmitoylphosphatidylcholine, dipalmitoyl oleoyl-phosphatidylcholine did not reduce the LPS activation of TLR4 signaling, indicating that these two abundant surfactant phospholipid species do not independently exert anti-inflammatory activity. In a separate study, Survanta was shown to inhibit LPS signaling in vitro by blocking translocation of TLR4 to lipid rafts in A549 cells (34). Future studies will determine if SP-C reconstituted with defined lipids redirects TLR4 localization in response to LPS.…”

Section: Discussionmentioning

confidence: 99%

Persistence of LPS-Induced Lung Inflammation in Surfactant Protein-C–Deficient Mice

Glasser

Maxfield²,

Ruetschilling³

et al. 2013

Am J Respir Cell Mol Biol

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Pulmonary surfactant protein-C (SP-C) gene-targeted mice (Sftpc 2/2 ) develop progressive lung inflammation and remodeling. We hypothesized that SP-C deficiency reduces the ability to suppress repetitive inflammatory injury. Sftpc 1/1 and Sftpc 2/2 mice given three doses of bacterial LPS developed airway and airspace inflammation, which was more intense in the Sftpc 2/2 mice at 3 and 5 days after the final dose. Compared with Sftpc 1/1 mice, inflammatory injury persisted in the lungs of Sftpc 2/2 mice 30 days after the final LPS challenge. Sftpc 2/2 mice showed LPS-induced airway goblet cell hyperplasia with increased detection of Sam pointed Ets domain and FoxA3 transcription factors. Sftpc 2/2 type II alveolar epithelial cells had increased cytokine expression after LPS exposure relative to Sftpc 1/1 cells, indicating that type II cell dysfunction contributes to inflammatory sensitivity. Microarray analyses of isolated type II cells identified a pattern of enhanced expression of inflammatory genes consistent with an intrinsic low-level inflammation resulting from SP-C deficiency. SP-C-containing clinical surfactant extract (Survanta) or SP-C/phospholipid vesicles blocked LPS signaling through the LPS receptor (Toll-like receptor [TLR] 4/CD14/MD2) in human embryonic kidney 293T cells, indicating that SP-C blocks LPS-induced cytokine production by a TLR4-dependent mechanism. Phospholipid vesicles alone did not modify the TLR4 response. In vivo deficiency of SP-C leads to inflammation, increased cytokine production by type II cells, and persistent inflammation after repetitive LPS stimulation.Keywords: surfactant protein-C; LPS; lung inflammation; type II cells; Toll-like receptor 4Surfactant protein-C (SP-C) is an abundant 3.5-kD surfactantassociated protein expressed and secreted by alveolar type II epithelial cells. The mature airspace form of SP-C is highly hydrophobic and palmitoylated at adjacent amino terminal cysteine residues (1). Mutations in the gene encoding human SP-C (SFTPC) have been shown to cause familial interstitial lung disease (ILD). Affected individuals express an altered proSP-C, leading to reduced levels of mature SP-C in the airspace (2-4). SP-C deficiencies without detectable mutations in the protein-coding region of SFTPC or due to promoter mutations have also been reported, and represent a true null condition (5-7). These individuals also develop ILD, including idiopathic pulmonary fibrosis (IPF). SP-C deficiency-related disease may arise as an acute childhood or as a late-onset disease in adulthood (3). Because SP-C is expressed exclusively in alveolar type II cells, the associated ILD/idiopathic pulmonary fibrosis presumably originates from a primary defect in the epithelium. SP-C deficiency increases susceptibility to viral-or bacterial-induced exacerbations in affected children (5,6,(8)(9)(10). SP-C-deficient mice (Sftpc 2/2 ) developed a strain-specific pulmonary phenotype with age that was similar to the human disease (11). Sftpc 2/2 mice were more susceptible to challenge with ...

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“…Toll-like receptors (TLRs) recognize highly conserved structural motifs from either pathogens or damaged and stressed tissues and are involved in microglial response to physiological and pathological signals. TLR4, in particular, reportedly mediates neuroprotective (1,2) and neurotoxic (3)(4)(5) effects, suggesting that TLR4 activation needs to be tightly controlled, to regulate the switch between its different roles in immune surveillance or neuroinflammatory propagation.…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective Effects of Toll-Like Receptor 4 Antagonism in Spinal Cord Cultures and in a Mouse Model of Motor Neuron Degeneration

Paola

Mariani

Bigini

et al. 2012

Mol Med

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Sustained inflammatory reactions are common pathological events associated with neuron loss in neurodegenerative diseases. Reported evidence suggests that Toll-like receptor 4 (TLR4) is a key player of neuroinflammation in several neurodegenerative diseases. However, the mechanisms by which TLR4 mediates neurotoxic signals remain poorly understood. We investigated the role of TLR4 in in vitro and in vivo settings of motor neuron degeneration. Using primary cultures from mouse spinal cords, we characterized both the proinflammatory and neurotoxic effects of TLR4 activation with lipopolysaccharide (activation of microglial cells, release of proinflammatory cytokines and motor neuron death) and the protective effects of a cyanobacteriaderived TLR4 antagonist (VB3323). With the use of TLR4-deficient cells, a critical role of the microglial component with functionally active TLR4 emerged in this setting. The in vivo experiments were carried out in a mouse model of spontaneous motor neuron degeneration, the wobbler mouse, where we preliminarily confirmed a protective effect of TLR4 antagonism. Compared with vehicle-and riluzole-treated mice, those chronically treated with VB3323 showed a decrease in microglial activation and morphological alterations of spinal cord neurons and a better performance in the paw abnormality and grip-strength tests. Taken together, our data add new understanding of the role of TLR4 in mediating neurotoxicity in the spinal cord and suggest that TLR4 antagonists could be considered in future studies as candidate protective agents for motor neurons in degenerative diseases.

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Surfactant lipids regulate LPS-induced interleukin-8 production in A549 lung epithelial cells by inhibiting translocation of TLR4 into lipid raft domains

Abstract: Supplementary key words lipopolysaccharide • cytokines • infl a mmationAs a primary interface between the lung and pathogens, the epithelial cells lining the airways and the alveoli are

Cited by 69 publications

References 67 publications

Combined Antibacterial and Anti-Inflammatory Activity of a Cationic Disubstituted Dexamethasone-Spermine Conjugate

Combined Antibacterial and Anti-Inflammatory Activity of a Cationic Disubstituted Dexamethasone-Spermine Conjugate

Persistence of LPS-Induced Lung Inflammation in Surfactant Protein-C–Deficient Mice

Neuroprotective Effects of Toll-Like Receptor 4 Antagonism in Spinal Cord Cultures and in a Mouse Model of Motor Neuron Degeneration

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