Differential Effects of Low- and High-dose Glucocorticoids on the Innate Immunity of Corneal Epithelium in Vitro

Xie, Xin; Yan, Xiaoran; Lin, Zhen; Jin, Xiuming

doi:10.3109/09273948.2011.569110

Cited by 6 publications

(4 citation statements)

References 34 publications

(38 reference statements)

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“…The local immunosuppression caused by topical glucocorticoids could be the result of an inhibition of innate defense mechanisms of epithelial cells and/or functions of professional immune cells. In support of these hypotheses, studies in humans and mice demonstrated that topical glucocorticoids are able to downregulate the expression of Toll‐like receptor 2 and Toll‐like receptor 4 by corneal epithelial cells and fibroblasts, reduce expression of antimicrobial peptides and reduce recruitment and activation of immune cells involved in innate and adaptive immunity …”

Section: Discussionmentioning

confidence: 94%

Localized demodicosis due to Demodex cati on the muzzle of two cats treated with inhalant glucocorticoids

Bizikova

2014

Veterinary Dermatology

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Section: Discussionmentioning

confidence: 94%

Localized demodicosis due to Demodex cati on the muzzle of two cats treated with inhalant glucocorticoids

Bizikova

2014

Veterinary Dermatology

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“…Glucocorticoid effects on human corneal epithelial cells have been previously reported for a few target genes (16,20,21), however, the genome wide actions of glucocorticoids have not been established. To address this issue, we performed western blotting in immortalized human corneal epithelial cell line to first determine if glucocorticoid receptor is expressed (18).…”

Section: Resultsmentioning

confidence: 99%

“…Opacification of the lens or cataract formation are also adverse events seen in sustained corticosteroid use. Glucocorticoids have also been reported to be synthesized in the human ocular surface and they have the ability to regulate corneal immune response (5-7). In the cornea, glucocorticoids have been shown to regulate their circadian rhythm (8,9), inhibit blood and lymphatic vessel growth (10,11), curb inflammation (12-15), and increase epithelial integrity under a hypoxic challenge (16), as well as retard wound healing in rabbits (17).…”

Section: Introductionmentioning

confidence: 99%

Glucocorticoid action in human corneal epithelial cells establishes roles for corticosteroids in wound healing and barrier function of the eye

Kadmiel

Jànoshàzi

et al. 2016

Experimental Eye Research

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Glucocorticoids play diverse roles in almost all physiological systems of the body, including both anti-inflammatory and immunosuppressive roles. Synthetic glucocorticoids are one of the most widely prescribed drugs and are used in the treatment of conditions such as autoimmune diseases, allergies, ocular disorders and certain types of cancers. In the interest of investigating glucocorticoid actions in the cornea of the eye, we established that multiple cell types in mouse corneas express functional glucocorticoid receptor (GR) with corneal epithelial cells having robust expression. To define glucocorticoid actions in a cell type-specific manner, we employed immortalized human corneal epithelial (HCE) cell line to define the glucocorticoid transcriptome and elucidated its functions in corneal epithelial cells. Over 4000 genes were significantly regulated within 6 hours of dexamethasone treatment, and genes associated with cell movement, cytoskeletal remodeling and permeability were highly regulated. Real-time in vitro wound healing assays revealed that glucocorticoids delay wound healing by attenuating cell migration. These functional alterations were associated with cytoskeletal remodeling at the wounded edge of a scratch-wounded monolayer. However, glucocorticoid treatment improved the organization of tight-junction proteins and enhanced the epithelial barrier function. Our results demonstrate that glucocorticoids profoundly alter corneal epithelial gene expression and many of these changes likely impact both wound healing and epithelial cell barrier function.

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“…Interestingly, low concentration of DEX induced a 3-fold increase in IL-1β production in unstimulated blood, whereas high concentration of DEX suppressed the production of this cytokine. Enhancement of innate immune responses by low concentrations of glucocorticoids, including TLR2 and -4 expression and IL-6, CXCL8 and IL-1 production, through upregulation of DUSP1 and de-phosphorylation of MAPK p38, have previously been reported [ 52 – 53 ].…”

Section: Discussionmentioning

confidence: 99%

Pentoxifylline, dexamethasone and azithromycin demonstrate distinct age-dependent and synergistic inhibition of TLR- and inflammasome-mediated cytokine production in human newborn and adult blood in vitro

Speer

Dowling

et al. 2018

PLoS ONE

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IntroductionNeonatal inflammation, mediated in part through Toll-like receptor (TLR) and inflammasome signaling, contributes to adverse outcomes including organ injury. Pentoxifylline (PTX), a phosphodiesterase inhibitor which potently suppresses cytokine production in newborn cord blood, is a candidate neonatal anti-inflammatory agent. We hypothesized that combinations of PTX with other anti-inflammatory agents, the steroid dexamethasone (DEX) or the macrolide azithromycin (AZI), may exert broader, more profound and/or synergistic anti-inflammatory activity towards neonatal TLR- and inflammasome-mediated cytokine production.MethodsWhole newborn and adult blood was treated with PTX (50–200 μM), DEX (10−10–10−7 M), or AZI (2.5–20 μM), alone or combined, and cultured with lipopolysaccharide (LPS) (TLR4 agonist), R848 (TLR7/8 agonist) or LPS/adenosine triphosphate (ATP) (inflammasome induction). Supernatant and intracellular cytokines, signaling molecules and mRNA were measured by multiplex assay, flow cytometry and real-time PCR. Drug interactions were assessed based on Loewe's additivity.ResultsPTX, DEX and AZI inhibited TLR- and/or inflammasome-mediated cytokine production in newborn and adult blood, whether added before, simultaneously or after TLR stimulation. PTX preferentially inhibited pro-inflammatory cytokines especially TNF. DEX inhibited IL-10 in newborn, and TNF, IL-1β, IL-6 and interferon-α in newborn and adult blood. AZI inhibited R848-induced TNF, IL-1β, IL-6 and IL-10, and LPS-induced IL-1β and IL-10. (PTX+DEX) synergistically decreased LPS- and LPS/ATP-induced TNF, IL-1β, and IL-6, and R848-induced IL-1β and interferon-α, while (PTX+AZI) synergistically decreased induction of TNF, IL-1β, and IL-6. Synergistic inhibition of TNF production by (PTX+DEX) was especially pronounced in newborn vs. adult blood and was accompanied by reduction of TNF mRNA and enhancement of IL10 mRNA.ConclusionsAge, agent, and specific drug-drug combinations exert distinct anti-inflammatory effects towards TLR- and/or inflammasome-mediated cytokine production in human newborn blood in vitro. Synergistic combinations of PTX, DEX and AZI may offer benefit for prevention and/or treatment of neonatal inflammatory conditions while potentially limiting drug exposure and toxicity.

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Differential Effects of Low- and High-dose Glucocorticoids on the Innate Immunity of Corneal Epithelium in Vitro

Abstract: Low-concentration hydrocortisone enhances the expression and function of TLRs in HCEC and provides evidence for a novel function of glucocorticoids in innate immunity.

Cited by 6 publications

References 34 publications

Localized demodicosis due to Demodex cati on the muzzle of two cats treated with inhalant glucocorticoids

Localized demodicosis due to Demodex cati on the muzzle of two cats treated with inhalant glucocorticoids

Glucocorticoid action in human corneal epithelial cells establishes roles for corticosteroids in wound healing and barrier function of the eye

Pentoxifylline, dexamethasone and azithromycin demonstrate distinct age-dependent and synergistic inhibition of TLR- and inflammasome-mediated cytokine production in human newborn and adult blood in vitro

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