Epidermal growth factor receptor inhibitors selectively inhibit the expressions of human β-defensins induced by Staphylococcus epidermidis

Park, Kio; Ommori, Rie; Imoto, Kyoko; Asada, Hideo

doi:10.1016/j.jdermsci.2014.04.011

Cited by 20 publications

(22 citation statements)

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“…Upregulation of hBD-3 (32, 33) and downregulation of hBD-9 (32) were found in the S. aureus-infected skin (33) and in the ocular surface of the patients with bacterial keratitis (32). The hBD-3 expression was increased during the first day of the infection and then was constant within the following 2 days, as was observed in the human S. aureus-infected epidermal keratinocytes (12).…”

Section: Discussionmentioning

confidence: 66%

“…PSMα‐induced G2/M‐transition delay was related to the decrease of the antibacterial functions of the epithelial cells. The expression level of antibacterial peptides such as human β‐defensins (hBDs), the first line of defense against staphylococcal infection (12), was lower in G2/M‐phase cells compared with cells in the G1 phase. We also tested clinical human S. aureus isolates and found that cell cycle delay activity was associated with PSMα1 production.…”

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confidence: 99%

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Phenol‐soluble modulinαinduces G2/M phase transition delay in eukaryotic HeLa cells

et al. 2015

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Staphylococcus aureus is a gram-positive bacterium responsible for a wide range of infections. Host cell cycle alteration is a sophisticated mechanism used by pathogens to hijack the defense functions of host cells. We previously demonstrated that S. aureus MW2 (USA400) bacteria induced a G2/M phase transition delay in HeLa cells. We demonstrate here that this activity is triggered by culture supernatant compounds. Using size exclusion chromatography of the MW2 supernatant, followed by mass spectroscopy analysis of corresponding peaks, we identified phenol-soluble modulin α (PSMα) peptides as the likely candidates for this effect. Indeed, synthetic PSMα1 and PSMα3 caused a G2/M phase transition delay. The implication of PSMα in cell cycle alteration was confirmed by comparison of S. aureus Los Angeles County clone (LAC) wild-type with the isogenic mutant LAC∆psmα, which lacks the psmα operon encoding PSMα1-4. PSMα-induced G2/M transition delay correlated with a decrease in the defensin genes expression suggesting a diminution of antibacterial functions of epithelial cells. By testing the supernatant of S. aureus human clinical isolates, we found that the degree of G2/M phase transition delay correlated with PSMα1 production. We show that PSMs secreted by S. aureus alter the host cell cycle, revealing a newly identified mechanism for fostering an infection.

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Section: Discussionmentioning

confidence: 66%

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confidence: 99%

Phenol‐soluble modulinαinduces G2/M phase transition delay in eukaryotic HeLa cells

et al. 2015

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“…They include hair loss, acneiform eruption, paronychia and xerosis. EGFR inhibition enhances the production and release of proinflammatory mediators, and inhibits the production of antimicrobial peptides, resulting in the development of inflammatory papules and pustules as well as an impaired host defence function 36 37 . Interestingly, in this study, rhEGF also inhibits the expression of TLR2 and proinflammatory cytokines increased by P. acnes through the inhibition of NF-κB, which is restored by using gefitinib.…”

Section: Discussionmentioning

confidence: 99%

Epidermal Growth Factor Attenuated the Expression of Inflammatory Cytokines in Human Epidermal Keratinocyte Exposed toPropionibacterium acnes

et al. 2018

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BackgroundWhile the beneficial effects of topical epidermal growth factor (EGF) on wound healing have been repeatedly reported, there are few reports about the effects of EGF on inflammatory skin diseases including acne.ObjectiveTo clarify the effects of EGF on acne, it was investigated whether recombinant human EGF (rhEGF) signalling can affect Propionibacterium acnes-induced cytokine expression in human epidermal keratinocytes.MethodsThe cultured normal human epidermal keratinocytes (NHK) were co-treated with P. acnes and rhEGF, and mRNA levels of interleukin (IL)-1α, IL-8 and tumor necrosis factor (TNF)-α; toll-like receptor 2 (TLR2); and nuclear factor kappa B (NF-κB) were determined. Specific enzyme-linked immunosorbent assay kits were used to measure the IL-1α, IL-8 and TLR2 expression as well as the NF-κB activation in P. acnes and rhEGF-treated NHK. After infecting the cultured NHK with live P. acnes, an increased expression of IL-1α, IL-8 and TNF-α was detected, which was prevented by rhEGF co-treatment.ResultsTLR2 and NF-κB activity increased after P. acnes treatment, and rhEGF treatment decreased TLR2 expression and NF-κB activity dose-dependently. The inhibition of EGF receptor by gefitinib attenuated the inhibitory effect of rhEGF on these increased expressions of proinflammatory cytokines and TLR2 and activity of NF-κB in NHK stimulated by P. acnes.ConclusionThese results suggest that EGF attenuated P. acnes-induced inflammatory responses, at least in part, through the modulation of TLR2 signalling, and the topical application of rhEGF may be beneficial to relieve the inflammatory reactions of acne.

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“…One of the most effective early responses of the host to pathogenic insults is mediated through human β-defensins (hBD). In vitro experiments with keratinocytes or skin explants have shown that S. epidermidis or its culture supernatants can elicit high levels of hBD-2 and hBD-3 but not hBD-1 (Lai et al, 2010 ; Li et al, 2013 ; Ommori et al, 2013 ; Percoco et al, 2013 ; Park et al, 2014 ), and RNase7 and cathelicidin LL-37 in epithelial cells (Burgey et al, 2016 ). This AMP induction may be beneficial under healthy conditions to counteract more pathogenic species (Lai et al, 2010 ; Li et al, 2013 ) but can be also expected to contribute to defense in S. epidermidis superficial or ocular infections.…”

Section: Host Interaction With S Epidermidismentioning

confidence: 99%

Pathogenic Mechanisms and Host Interactions in Staphylococcus epidermidis Device-Related Infection

et al. 2017

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Staphylococcus epidermidis is a permanent member of the normal human microbiota, commonly found on skin and mucous membranes. By adhering to tissue surface moieties of the host via specific adhesins, S. epidermidis is capable of establishing a lifelong commensal relationship with humans that begins early in life. In its role as a commensal organism, S. epidermidis is thought to provide benefits to human host, including out-competing more virulent pathogens. However, largely due to its capacity to form biofilm on implanted foreign bodies, S. epidermidis has emerged as an important opportunistic pathogen in patients receiving medical devices. S. epidermidis causes approximately 20% of all orthopedic device-related infections (ODRIs), increasing up to 50% in late-developing infections. Despite this prevalence, it remains underrepresented in the scientific literature, in particular lagging behind the study of the S. aureus. This review aims to provide an overview of the interactions of S. epidermidis with the human host, both as a commensal and as a pathogen. The mechanisms retained by S. epidermidis that enable colonization of human skin as well as invasive infection, will be described, with a particular focus upon biofilm formation. The host immune responses to these infections are also described, including how S. epidermidis seems to trigger low levels of pro-inflammatory cytokines and high levels of interleukin-10, which may contribute to the sub-acute and persistent nature often associated with these infections. The adaptive immune response to S. epidermidis remains poorly described, and represents an area which may provide significant new discoveries in the coming years.

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Epidermal growth factor receptor inhibitors selectively inhibit the expressions of human β-defensins induced by Staphylococcus epidermidis

Abstract: EGFRIs may cause cutaneous adverse effects through selectively perturbing innate immune responses induced by commensal and pathogenic bacteria.

Cited by 20 publications

References 11 publications

Phenol‐soluble modulinαinduces G2/M phase transition delay in eukaryotic HeLa cells

Phenol‐soluble modulinαinduces G2/M phase transition delay in eukaryotic HeLa cells

Epidermal Growth Factor Attenuated the Expression of Inflammatory Cytokines in Human Epidermal Keratinocyte Exposed toPropionibacterium acnes

Pathogenic Mechanisms and Host Interactions in Staphylococcus epidermidis Device-Related Infection

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