Defensin Expression by the Cornea: Multiple Signalling Pathways Mediate IL-1β Stimulation of hBD-2 Expression by Human Corneal Epithelial Cells

McDermott, Alison M.; Redfern, Rachel L.; Zhang, Bei; Pei, Ying; Li-min, Huang; Proske, Rita J.

doi:10.1167/iovs.02-0787

Cited by 170 publications

(167 citation statements)

References 42 publications

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“…Induction of defensin synthesis may involve several cascades, including p38MAPK and NFκB pathways (28)(29)(30)(31). As demonstrated by our results, highglucose conditions reduced constitutive phosphorylated p38MAPK expression but has a limited impact on active NFκB binding.…”

Section: Discussionsupporting

confidence: 73%

High-Glucose Environment Inhibits p38MAPK Signaling and Reduces Human β-3 Expression in Keratinocytes

Lan

Huang

et al. 2011

Mol Med

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Diabetes mellitus is characterized by elevated plasma glucose and increased rates of skin infections. Altered immune responses have been suggested to contribute to this prevalent complication, which involves microbial invasion. In this study we explored the effects of a high-glucose environment on the innate immunity of keratinocytes by focusing on β defensin-3 (BD3) using in vivo and in vitro models. Our results demonstrated that the perilesional skins of diabetic rats failed to show enhanced BD3 expression after wounding. In addition, high-glucose treatment reduced human BD3 (hBD3) expression of cultured human keratinocytes. This pathogenic process involved inhibition of p38MAPK signaling, an event that resulted from increased formation of advanced glycation end products. On the other hand, toll-like receptor-2 expression and function of cultured keratinocytes were not significantly affected by high-glucose treatment. In summary, high-glucose conditions inhibited the BD3 expression of epidermal keratinocytes, which in turn contributed to the frequent occurrences of infection associated with diabetic wounding.

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Section: Discussionsupporting

confidence: 73%

High-Glucose Environment Inhibits p38MAPK Signaling and Reduces Human β-3 Expression in Keratinocytes

Lan

Huang

et al. 2011

Mol Med

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“…17,18 Human β-defensin-1 (hBD-1) and hBD-3 are constitutively expressed by the corneal and conjunctival epithelia, 18-20 whereas the expression of hBD-2 is inducible by proinflammatory cytokines such as IL-1α, IL-1β, TNF-α, bacterial by-products such as lipopolysaccharide and heat-killed Pseudomonas aeruginosa, and injury. [19][20][21][22] We have also observed that hBD-2 is expressed by conjunctival epithelial cells from patients with moderate dry eye but not in cells from normal subjects. 20 Because it has been reported that proinflammatory cytokines are secreted in greater amounts by HCECs in hyperosmolar media, 10 we reasoned that a differential expression of β-defensins by HCECs may be observed when the cells are in a hyperosmolar environment.…”

mentioning

confidence: 58%

“…When confluent, cells were passed using standard trypsin-EDTA methods. P-HCECs of passages 1 to 2 and SV40-HCECs of passages 18,19,22,26, and 31 were used in the experiments.…”

Section: Cell Culturementioning

confidence: 99%

Effect of Hyperosmolality on β-Defensin Gene Expression by Human Corneal Epithelial Cells

Narayanan

Manning²,

Proske³

et al. 2006

Cornea

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Purpose-As human β-defensins (hBD) are important antimicrobial peptides at epithelial surfaces, including the ocular surface, we tested the effect of hyperosmolar conditions on the expression of these peptides by human corneal epithelial cells (HCECs).Methods-Simian virus 40-transformed HCECs (n = 5) or primary cultured HCECs (n = 5) were treated with serum-free media or serum-free hyperosmolar (400-500 mOsm/kg) media for 24 hours or serum-free 500 mOsm/kg media for 12 to 48 hours. The effect of hyperosmolality on interleukin-1β (IL-1β)-induced hBD-2 expression was also tested. IL-6 expression was studied as a marker of IL-1β function. Expression of hBD-1, -2, and -3 and IL-6 mRNA was detected by reverse transcription-polymerase chain reaction (RT-PCR). The levels of active IL-1β (culture supernatants and cell lysates) and pro-IL-1β (cell lysates) were detected by enzyme-linked immunosorbent assay.Results-HCECs constitutively expressed hBD-1 and -3 but not hBD-2. Hyperosmolar media had no effect on the basal expression of hBD-1 or -3 and did not induce the expression of hBD-2. Treatment with 500 mOsm/kg media for 24 hours decreased the ability of IL-1β to upregulate hBD-2 and IL-6 expression. Active or pro-IL-1β was not detected in any cell culture sample.Conclusion-Our results suggest that the hyperosmolar environment observed in diseases such as dry eye does not alter defensin expression. However, a hyperosmolar environment may influence cytokine function in ocular surface cells and thus affect their response to injury and inflammation. Keywords hyperosmolality; human β-defensins; corneal epithelium; cytokines Hyperosmolality at the ocular surface is a characteristic of diseases such as dry eye and diabetes mellitus. The normal osmolality of the tear fluid is approximately 300 mOsm/kg, 1 whereas the suggested "gold standard" diagnostic of dry eye is 312 mOsm/kg or greater. 2 It has been proposed that tear fluid hyperosmolality occurs because of either normal tear evaporation associated with reduced tear flow or excessive tear evaporation with a normal tear flow. 3 The hyperosmolar tear film is thought to affect ocular surface epithelial function and differentiation in dry eye disease, with osmolalities as high as 417 mOsm/kg being reported. 1,4,5 Also, Aragona et al 6 showed that type 1 diabetic patients had a significantly higher mean tear osmolality (332.2 ± 18.3 mOsm/L), poor tear stability, altered tear function, and symptoms of ocular irritation akin to patients with dry eye than normal patients. Hyperosmolality in diabetes mellitus is probably attributable to increased levels of tear glucose seen in patients with both types 1 and 2. 7

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“…IL-1␤ has also been reported to be a major activator of hBD-2 expression in A549 cells cultured with mononuclear phagocytes (24). Furthermore, IL-1␣ and IL-1␤ have both been reported to stimulate the expression of hBD-2 in various tissues (19,54,55). It is thus reasonable to hypothesize that the IL-17 effect on hBD-2 gene expression be mediated in an autocrine/paracrine manner via locally secreted IL-1.…”

Section: Discussionmentioning

confidence: 99%

IL-17 Markedly Up-Regulates β-Defensin-2 Expression in Human Airway Epithelium via JAK and NF-κB Signaling Pathways

Kao

Chen

Thai

et al. 2004

The Journal of Immunology

370

314

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Using microarray gene expression analysis, we first observed a profound elevation of human β-defensin-2 (hBD-2) message in IL-17-treated primary human airway epithelial cells. Further comparison of this stimulation with a panel of cytokines (IL-1α, 1β, 2–13, and 15–18; IFN-γ; GM-CSF; and TNF-α) demonstrated that IL-17 was the most potent cytokine to induce hBD-2 message (>75-fold). IL-17-induced stimulation of hBD-2 was time and dose dependent, and this stimulation also occurred at the protein level. Further studies demonstrated that hBD-2 stimulation was attenuated by IL-17R-specific Ab, but not by IL-1R antagonist or the neutralizing anti-IL-6 Ab. This suggests an IL-17R-mediated signaling pathway rather than an IL-17-induced IL-1αβ and/or IL-6 autocrine/paracrine loop. hBD-2 stimulation was sensitive to the inhibition of the JAK pathway, and to the inhibitors that affect NF-κB translocation and the DNA-binding activity of its p65 NF-κB subunit. Transient transfection of airway epithelial cells with an hBD-2 promoter-luciferase reporter gene expression construct demonstrated that IL-17 stimulated promoter-reporter gene activity, suggesting a transcriptional mechanism for hBD-2 induction. These results support an IL-17R-mediated signaling pathway involving JAK and NF-κB in the transcriptional stimulation of hBD-2 gene expression in airway epithelium. Because IL-17 has been identified in a number of airway diseases, especially diseases related to microbial infection, these findings provide a new insight into how IL-17 may play an important link between innate and adaptive immunity, thereby combating infection locally within the airway epithelium.

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Defensin Expression by the Cornea: Multiple Signalling Pathways Mediate IL-1β Stimulation of hBD-2 Expression by Human Corneal Epithelial Cells

Cited by 170 publications

References 42 publications

High-Glucose Environment Inhibits p38MAPK Signaling and Reduces Human β-3 Expression in Keratinocytes

High-Glucose Environment Inhibits p38MAPK Signaling and Reduces Human β-3 Expression in Keratinocytes

Effect of Hyperosmolality on β-Defensin Gene Expression by Human Corneal Epithelial Cells

IL-17 Markedly Up-Regulates β-Defensin-2 Expression in Human Airway Epithelium via JAK and NF-κB Signaling Pathways

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