Down‐regulation of <scp>IL</scp>‐8 by high‐dose vitamin <scp>D</scp> is specific to hyperinflammatory macrophages and involves mechanisms beyond up‐regulation of <scp><i>DUSP1</i></scp>

Dauletbaev, Nurlan; Herscovitch, Kassey; Das, Mithun; Chen, H; Bernier, Joanie; Matouk, Elias; Bérubé, Julie; Rousseau, Stéphane; Lands, Larry C.

doi:10.1111/bph.13249

Cited by 54 publications

(47 citation statements)

References 42 publications

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“…This is in contrast to other studies on respiratory pathogens including tuberculosis where vitamin D had no effect on neutrophilia29. Similarly, vitamin D has been shown down-regulate IL-8 release in hyper-inflammatory macrophages21. The disparities in these observations suggest that the impact of vitamin D on the production of IL-8 by innate immune cells is dependent on the cell that is producing the cytokine and the infectious stimulus.…”

Section: Discussionmentioning

confidence: 71%

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Vitamin D both facilitates and attenuates the cellular response to lipopolysaccharide

Chen

Eapen

Zosky

2017

Sci Rep

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Vitamin D has a range of non-skeletal health effects and has been implicated in the response to respiratory infections. The aim of this study was to assess the effect of vitamin D on the response of epithelial cells, neutrophils and macrophages to lipopolysaccharide (LPS) stimulation. BEAS-2B cells (airway epithelial cell line) and primary neutrophils and macrophages isolated from blood samples were cultured and exposed to LPS with and without vitamin D (1,25(OH)2D). The production of IL-6, IL-8, IL-1β and TNF-α of all cells and the phagocytic capacity of neutrophils and macrophages to E. coli were assessed. Vitamin D had no effect on BEAS-2B cells but enhanced the production of IL-8 in neutrophils (p = 0.007) and IL-1β in macrophages (p = 0.007) in response to LPS. Both vitamin D (p = 0.019) and LPS (p < 0.001) reduced the phagocytic capacity of macrophages. These data suggest that the impact of vitamin D on responses to infection are complex and that the net effect will depend on the cells that respond, the key response that is necessary for resolution of infection (cytokine production or phagocytosis) and whether there is pre-existing inflammation.

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Section: Discussionmentioning

confidence: 71%

“…IL-1β and TNF-α are essential for the activation of the epithelium and downstream inflammatory responses19. In addition, IL-1β, IL-6, IL-8 and TNF-α are involved in the innate immune responses by neutrophils and macrophages20 and may be influenced by vitamin D16171821.…”

mentioning

confidence: 99%

Vitamin D both facilitates and attenuates the cellular response to lipopolysaccharide

Chen

Eapen

Zosky

2017

Sci Rep

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“…Alterations in the IL-8 production by human CF macrophages have been consistently documented even though airway epithelial cells are the source of most IL-8 in the lung. In particular, IL-8 production between non CF and CF human M-MDMs showed no difference in response to LPS stimulation, however significantly higher constitutive IL-8 production in CF MDMs compared to non CF cells was observed [23,49]. Accordingly, higher levels of IL-8 mRNA were detected in human AMs isolated from CF children free of any bacterial colonization [50].…”

Section: Human Cf Macrophage Inflammatory Phenotypementioning

confidence: 92%

The impact of impaired macrophage functions in cystic fibrosis disease progression

Lévêque

Trionnaire

Porto³

et al. 2017

Journal of Cystic Fibrosis

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The underlying cause of morbidity in cystic fibrosis (CF) is the decline in lung function, which results in part from chronic inflammation. Inflammation and infection occur early in infancy in CF and the role of innate immune defense in CF has been highlighted in the last years. Once thought simply to be consumers of bacteria, macrophages have emerged as highly sensitive immune cells that are located at the balance point between inflammation and resolution of this inflammation in CF pathophysiology. In order to assess the potential role of macrophage in CF, we review the evidence that: (1) CF macrophage has a dysregulated inflammatory phenotype; (2) CF macrophage presents altered phagocytosis capacity and bacterial killing; and (3) lipid disorders in CF macrophage affect its function. These alterations of macrophage weaken innate defense of CF patients and may be involved in CF disease progression and lung damage.

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“…Supplies for NF-kB reporter assay were as in our prior studies (26,27 . Gel electrophoresis and transfer supplies were as indicated in our recent publication (28). All other supplies were from Sigma-Aldrich (Mississauga, ON, Canada).…”

Section: Reagentsmentioning

confidence: 99%

Stimulation of the RIG-I/MAVS Pathway by Polyinosinic:Polycytidylic Acid Upregulates IFN-β in Airway Epithelial Cells with Minimal Costimulation of IL-8

Dauletbaev

Cammisano

Herscovitch

et al. 2015

The Journal of Immunology

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Pharmacological stimulation of the antiviral cytokine IFN-β in the airways may help to counter deleterious virus-induced exacerbations in chronic inflammatory lung diseases (asthma, chronic obstructive pulmonary disease, or cystic fibrosis). Polyinosinic-polycytidylic acid [poly(I:C)] is a known inducer of IFN-β but also costimulates an inflammatory response. The latter response is undesirable given the pre-existing airway inflammation in these diseases. The objective of our study was to identify conditions for poly(I:C) to selectively upregulate IFN-β in airway epithelial cells without a concomitant inflammatory response. The inflammatory response was gauged by production of the chemokine IL-8. Using cell lines and primary airway epithelial cells (both submerged and well-differentiated), we observed that pure poly(I:C) stimulated IFN-β mainly through the TLR3/TRIF pathway and IL-8 through an unidentified pathway. The magnitude of the IL-8 response stimulated by pure poly(I:C) matched or even exceeded that of IFN-β. Furthermore, this IL-8 response could not be pharmacologically downregulated without affecting IFN-β. In contrast, we show that stimulation of the RIG-I/MAVS pathway, such as when poly(I:C) is delivered intracellularly in a complex with liposomes or via nucleofection, selectively stimulates IFN-β with low IL-8 costimulation. The magnitude of IFN-β stimulation by liposome-encapsulated poly(I:C) is markedly diminished in well-differentiated cells. In conclusion, it is feasible to augment IFN-β production in airway epithelial cells without excessive costimulation of IL-8 if the RIG-I/MAVS pathway is stimulated, such as via liposomal delivery of poly(I:C). Better cytoplasmic delivery vehicles are needed to efficiently stimulate this pathway in well-differentiated cells.

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Down‐regulation of IL‐8 by high‐dose vitamin D is specific to hyperinflammatory macrophages and involves mechanisms beyond up‐regulation of DUSP1

Cited by 54 publications

References 42 publications

Vitamin D both facilitates and attenuates the cellular response to lipopolysaccharide

Vitamin D both facilitates and attenuates the cellular response to lipopolysaccharide

The impact of impaired macrophage functions in cystic fibrosis disease progression

Stimulation of the RIG-I/MAVS Pathway by Polyinosinic:Polycytidylic Acid Upregulates IFN-β in Airway Epithelial Cells with Minimal Costimulation of IL-8

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