Dataset Information

L-Ascorbyl-2-phosphate attenuates NF-?B signaling in SZ95 sebocytes without affecting IL-6 and IL-8 secretion.

ABSTRACT: Acne is the most common inflammatory skin disease. Interleukin-1 (IL-1) is at the beginning of the cytokine signaling cascade and may be involved in the pathogenesis of this disorder. It activates redox-sensitive transcription factors, which induce IL-6 and IL-8 expression. Interestingly, L-ascorbyl-2-phosphate (APS) was shown to have beneficial effects in patients with acne vulgaris. The mechanism of action of this agent remains unknown. Here, we investigated if APS attenuates IL-1?- or TNF-?-mediated IL-6 and IL-8 expression in SZ95 sebocytes, whereas TNF-? was used as control. We also explored NF-?B activation which is known to orchestrate IL-1?- and TNF-?-mediated cytokine expression in many cell types. Both IL-1? and TNF-? increased IL-6 and IL-8 mRNA expression in SZ95 sebocytes. However, only IL-1? induced IL-6 and IL-8 secretion. IL-1? but not TNF-? activated NF-?B canonical signaling as demonstrated by I?-B? phosphorylation and degradation as well as by nuclear accumulation of NF-?B/p65. Concomitant treatment of SZ95 sebocytes with APS attenuated the effect of IL-1? and TNF-? on IL-6 and IL-8 gene expression as well as on IL-1?-mediated NF-?B signaling. In contrast, APS failed to reduce IL-1?-mediated IL-6 and IL-8 secretion, presumably by maintained IL-1?-mediated p38 activation, which is known to control IL-8 secretion. Our findings shed light into the impact of IL-1? on the inflammatory cytokine response and its molecular mechanisms in human sebocytes. Our data further suggest that the beneficial effect of APS in acne patients involves attenuation of NF-?B signaling but not reduction of IL-6 or IL-8 secretion.

SUBMITTER: Ikeno H

PROVIDER: S-EPMC4540786 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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L-Ascorbyl-2-phosphate attenuates NF-κB signaling in SZ95 sebocytes without affecting IL-6 and IL-8 secretion.

Ikeno Hiroshi H Apel Mara M Zouboulis Christos C Luger Thomas A TA Böhm Markus M

Archives of dermatological research 20150418 7

Acne is the most common inflammatory skin disease. Interleukin-1 (IL-1) is at the beginning of the cytokine signaling cascade and may be involved in the pathogenesis of this disorder. It activates redox-sensitive transcription factors, which induce IL-6 and IL-8 expression. Interestingly, L-ascorbyl-2-phosphate (APS) was shown to have beneficial effects in patients with acne vulgaris. The mechanism of action of this agent remains unknown. Here, we investigated if APS attenuates IL-1β- or TNF-α-m ...[more]

PMID: 25894228

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Project description:Epidermal growth factor (EGF) acts as a paracrine and autocrine mediator of cell proliferation and differentiation in various types of epithelial cells, such as sebocytes, which produce the lipid-rich sebum to moisturize the skin. However, sebum lipids via direct contact and by penetrating through the epidermis may have regulatory roles on epidermal and dermal cells as well. As EGF receptor (EGFR) is expressed throughout the proliferating and the lipid-producing layers of sebaceous glands (SGs) in healthy and acne-involved skin, we investigated the effect of EGF on SZ95 sebocytes and how it may alter the changes induced by palmitic acid (PA), a major sebum component with bioactive roles. We found that EGF is not only a potent stimulator of sebocyte proliferation, but also induces the secretion of interleukin (IL)6 and down-regulates the expression of genes involved in steroid and retinoid metabolism. Importantly, when applied in combination with PA, the PA-induced lipid accumulation was decreased and the cells secreted increased IL6 levels. Functional clustering of the differentially regulated genes in SZ95 sebocytes treated with EGF, PA or co-treated with EGF+PA further confirmed that EGF may be a potent inducer of hyperproliferative/inflammatory pathways (IL1 signaling), an effect being more pronounced in the presence of PA. However, while a group of inflammatory genes was up-regulated significantly in EGF+PA co-treated sebocytes, PA treatment in the absence of EGF, regulated genes only related to cell homeostasis. Meta-analysis of the gene expression profiles of whole acne tissue samples and EGF- and EGF+PA -treated SZ95 sebocytes showed that the EGF+PA co-activation of sebocytes may also have implications in disease. Altogether, our results reveal that PA-induced lipid accumulation and inflammation can be modulated by EGF in sebocytes, which also highlights the need for system biological approaches to better understand sebaceous (immuno)biology.

Project description:The polymorphic membrane protein D (Pmp18D) is a 160-kDa outer membrane protein that is conserved and plays an important role in Chlamydia abortus pathogenesis. We have identified an N-terminal fragment of Pmp18D (designated Pmp18.1) as a possible subunit vaccine antigen. In this study, we evaluated the vaccine potential of Pmp18.1 by investigating its ability to induce innate immune responses in dendritic cells and the signaling pathway(s) involved in rPmp18.1-induced IL-1β secretion. We next investigated the immunomodulatory impact of VCG, in comparison with the more established Th1-promoting adjuvants, CpG and FL, on rPmp18.1-mediated innate immune activation. Finally, the effect of siRNA targeting TLR4, MyD88, NF-κB p50, and Caspase-1 mRNA in DCs on IL-1β cytokine secretion was also investigated. Bone marrow-derived dendritic cells (BMDCs) were stimulated with rPmp18.1 in the presence or absence of VCG or CpG or FL and the magnitude of cytokines produced was assessed using a multiplex cytokine ELISA assay. Expression of costimulatory molecules and Toll-like receptors (TLRs) was analyzed by flow cytometry. Quantitation of intracellular levels of myeloid differentiation factor 88 (MyD88), nuclear factor kappa beta (NF-κB p50/p65), and Caspase-1 was evaluated by Western immunoblotting analysis while NF-κB p65 nuclear translocation was assessed by confocal microscopy. The results showed DC stimulation with rPmp18.1 provoked the secretion of proinflammatory cytokines and upregulated expression of TLRs and co-stimulatory molecules associated with DC maturation. These responses were significantly (p ≤ 0.001) enhanced by VCG but not CpG or FL. In addition, rPmp18.1 activated the expression of MyD88, NF-κB p50, and Caspase-1 as well as the nuclear expression of NF-κB p65 in treated DCs. Furthermore, targeting TLR4, MyD88, NF-κB p50, and Caspase-1 mRNA in BMDCs with siRNA significantly reduced their expression levels, resulting in decreased IL-1β cytokine secretion, strongly suggesting their involvement in the rPmp18.1-induced IL-1β cytokine secretion. Taken together, these results indicate that C. abortus Pmp18.1 induces IL-1β secretion by TLR4 activation through the MyD88, NF-κB as well as the Caspase-1 signaling pathways and may be a potential C. abortus vaccine candidate. The vaccine potential of Pmp18.1 will subsequently be evaluated in an appropriate animal model, using VCG as an immunomodulator, following immunization and challenge.

Dataset Information

L-Ascorbyl-2-phosphate attenuates NF-?B signaling in SZ95 sebocytes without affecting IL-6 and IL-8 secretion.

Publications

L-Ascorbyl-2-phosphate attenuates NF-κB signaling in SZ95 sebocytes without affecting IL-6 and IL-8 secretion.

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