SZ95 Sebocytes Research Articles

Enhancement of lipid content and inflammatory cytokine secretion in SZ95 sebocytes by palmitic acid suggests a potential link between free fatty acids and acne aggravation.

A relationship between acne and free fatty acids (FFAs) has been suggested recently. However, the effects of FFAs on sebaceous glands are still largely unknown. At the same time, the role of FFAs during chronic inflammation is well established. Considering that FFAs are also a major component of sebum, it is likely that changes in FFA affect both the synthesis of sebum and the inflammatory response in sebaceous glands. In this study, we examined a hypothesis that FFAs increase the production of sebum and induce inflammation in the sebaceous glands. We found that treatment of SZ95 sebocytes with exogenously applied palmitic acid (PA), a major saturated FFA, induced a significant increase in intracellular lipid levels. Moreover, PA treatment also increased the expression and secretion of the proinflammatory cytokines in SZ95 sebocytes. We also found that Toll-like receptors were required for the inflammatory response triggered by PA. The results of our study strengthen the notion about the link between acne and FFAs and suggest the mechanism underlying this relationship. Our results serve as a foundation for future work that will explore the association between FFA and acne and pave way to the development of novel treatment options for acne.

Effects of Eupatilin on Insulin-Like Growth Factor 1-Induced Lipogenesis and Inflammation of SZ95 Sebocytes.

Effects of Eupatilin on Insulin-Like Growth Factor 1-Induced Lipogenesis and Inflammation of SZ95 Sebocytes.

Licochalcone A attenuates acne symptoms mediated by suppression of NLRP3 inflammasome.

Activation of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome by Propionibacterium acnes (P.acnes) is critical for inducing inflammation and aggravating the development of acne lesions. We searched for available small-molecule inhibitors of the NLRP3 inflammasome that could be topically administered for the treatment of acne. We found that licochalcone A, a chalconoid isolated from the root of Glycyrrhiza inflate, was an effective inhibitor for P.acnes-induced NLRP3 inflammasome activation. Licochalcone A blocked P.acnes-induced production of caspase-1(p10) and IL-1β in primary mouse macrophages and human SZ95 sebocytes, indicating the suppression of NLRP3 inflammasome. Licochalcone A suppressed P.acnes-induced ASC speck formation and mitochondrial reactive oxygen species. Topical application of licochalcone A to mouse ear skin attenuated P.acnes-induced skin inflammation as shown by histological assessment, ear thickness measurement, and inflammatory gene expression. Licochalcone A reduced caspase-1 activity and IL-1β production in mouse ear injected with P.acnes. This study demonstrated that licochalcone A is effective in the control of P.acnes-induced skin inflammation as an efficient inhibitor for NLRP3 inflammasome. Our study provides a new paradigm for the development of anti-acne therapy via targeting NLRP3 inflammasome.

Aryl Hydrocarbon Receptor Modulates the Expression of TNF-α and IL-8 in Human Sebocytes via the MyD88-p65NF-κB/p38MAPK Signaling Pathways

Activation of Toll-like receptor (TLR)-2 and subsequent inflammatory response contribute to lesion development in acne vulgaris. A cross-talk between aryl hydrocarbon receptor (AhR), a cytosolic receptor protein that responds to environmental and physiological stress, and TLRs has recently been reported. In this study, we explored the possible role of AhR in the effects induced on cultured human SZ95 sebocytes by peptidoglycan (PGN), a classic TLR2 agonist. PGN-induced secretion of inflammatory factors TNF-α and IL-8 in human SZ95 sebocytes was suppressed after knockdown of AhR and pretreatment with the AhR antagonist CH223191. In addition, the AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) enhanced TNF-α and IL-8 secretion in PGN-pretreated sebocytes. Furthermore, PGN-induced expression of myeloid differentiation factor 88 (MyD88), phospho-p38MAPK (p-p38MAPK), and p-p65NF-κB was strengthened by TCDD and repressed by CH223191. AhR inhibition by transfecting shRNA blocked the ability of PGN to stimulate phosphorylation of p38MAPK and p65NF-κB in SZ95 sebocytes. Overall, these data demonstrate that AhR is able to modulate PGN-induced expression of TNF-α and IL-8 in human SZ95 sebocytes involving the MyD88-p65NF-κB/p38MAPK signaling pathway, which probably indicates a new mechanism in TLR2-mediated acne.

Is Human Sebum the Source of Skin Follicular Ultraviolet-Induced Red Fluorescence? A Cellular to Histological Study

Background: The ultraviolet-induced red fluorescence (UVRF) from human skin follicles was suggested to be a result of Propionibacterium acnes and was used for the monitoring of acne. More recent studies suggested that the UVRF may be more related to sebum rather than to microorganisms. Objective: To clarify whether human sebum or follicular microorganisms are the source of UVRF. Methods: We examined the fluorescence of human-derived SZ95 sebocytes, human sebaceous glands, sebum extracted from the sebaceous glands, and bacteria isolated from human hair follicles under ultraviolet light. Results: SZ95 sebocytes, human sebaceous glands, and sebum do not emit UVRF. Two types of UVRF peaking at about 635 nm and at about 620 nm were detected in P. acnes and Staphylococcus epidermidis, respectively. This is the first report that S. epidermidis emits UVRF when it is anaerobically cultured and then exposed to air. Conclusion: Human follicular UVRF is emitted by resident bacteria, not by sebum. Therefore, UVRF may be used to monitor certain species of skin microorganisms.

ALA-PDT suppressed the cell growth by Akt-/Erk-mTOR-p70 s6k pathway in human SZ95 sebocytes in vitro.

Topical 5-aminolevulinic acid mediated photodynamic therapy (PDT) is known to be an effective method in treating acne vulgaris and other sebaceous gland-related diseases. The therapeutic mechanisms of ALA-PDT still remain undetermined. Our team has reported that ALA-PDT suppressed the cell growth in SZ95 sebocytes by mTOR-p70 S6K signaling. In this study, we aimed to investigate upstream of the mammalian target of rapamycin (mTOR) signaling cascade after ALA-PDT on cell growth of human SZ95 sebocytes. Human SZ95 sebocytes were treated with different concentration of 5-ALA PDT. Western blotting was used to detect and analyze the protein expression level of P-Akt (T308)/Akt, P-Akt (S473)/Akt, P-Erk/Erk, P-AMPKα (T172)/AMPK, P-AMPKα1 (S485)/AMPKα2 (S491)/AMPK, P-PRAS40/PRAS40, RagC. Meanwhile, mTOR pathway activator IGF-1 and mTORC1 inhibitor rapamycin were added to observe the interferences of P-p70 S6K/p70 S6K after ALA-PDT. mTOR pathway inhibitor rapamycin decreased the level of P-p70 S6K reduced by ALA-PDT. Conversely, mTOR pathway activator IGF-1. ALA-PDT reduced the level of P-Akt (T308), P-Erk, P-AMPKα (T172), P-AMPKα1 (S485)/AMPKα2 (S491) and P-PRAS40, and no change was observed in the level of Rag C. ALA-PDT suppresses the cell growth in SZ95 cells through Akt-/Erk- mTOR -p70 s6k pathway rather than PRAS40-/RagC- mTOR pathway.

Genome wide analysis of TLR1/2- and TLR4-activated SZ95 sebocytes reveals a complex immune-competence and identifies serum amyloid A as a marker for activated sebaceous glands.

Toll-like receptors (TLR) 2 and 4 are active in sebaceous glands and play a central role in the development of acne. Still, there is only limited knowledge on their effect on sebocytes. In this work we performed global gene expression profile analysis with functional clustering of the differentially regulated genes of TLR1/2 (PAM3CSK4)- and TLR4 (lipopolysaccharide [LPS])-activated SZ95 sebocytes. Both TLR1/2- and 4-activation promoted inflammation in a similar manner already at an early time-point (6 hours), regulating genes involved in inflammation, wound healing and chemotaxis reflecting a more complex cytokine and chemokine regulation than previously known. Importantly, lipid metabolism, the primary feature of sebocytes, was affected at the level of gene expression only at a later time point (24 hours) indicating that sebocytes prioritize to exert a pro-inflammatory phenotype when confronted with a danger signal. Supporting the biological relevance of our results, a meta-analysis revealed that the genes showing the strongest up-regulation were also found up-regulated in acne. Of these genes, serum amyloid A 1/2 (SAA1/2) was confirmed to be a suitable protein marker for in vivo activated sebocytes, underlining their immune-competence, which is structurally defined within sebaceous glands of acne and rosacea skin samples. Altogether our findings demonstrate that sebocytes are not only positioned at the end point of inflammation but are actively involved in shaping the inflammatory response with putative diagnostic and therapeutic relevance.

Demodex mites modulate sebocyte immune reaction: possible role in the pathogenesis of rosacea

Rosacea is a common facial skin disorder mainly affecting middle-aged adults. Its aetiology is unknown and pathogenesis uncertain. Activation of the host innate immune response has been identified as an important factor. The Demodex mite population in the skin of rosacea patients is significantly higher than in patients with normal skin, suggesting that they may be of aetiological importance in this disorder. To determine the potential of Demodex mites to interact with the host immune system. Live Demodex mites were extracted from normal facial skin of control subjects and used in cell stimulation experiments with the immortalized SZ95 sebocyte line. Time- and mite-dose-dependent experiments were performed. Direct effects of Demodex and effects of the medium in which Demodex had been cultured were evaluated on the Toll-like receptor (TLR) signalling pathway on both a gene and protein expression level. Mites modulated TLR signalling events on both mRNA and protein levels in SZ95 sebocytes. An initial trend towards downmodulation of genes in this pathway was observed. A subsequent switch to positive gene upregulation was recorded after 48 h of coculture. Demodex secreted bioactive molecules that affected TLR2 receptor expression by sebocytes. High numbers of Demodex induced proinflammatory cytokine secretion, whereas lower numbers did not. Demodex mites have the capacity to modulate the TLR signalling pathway of an immortalized human sebocyte line. Mites have the capacity to secrete bioactive molecules that affect the immune reactivity of sebocytes. Increasing mite numbers influenced interleukin-8 secretion by these cells.

Endocannabinoid Tone Regulates Human Sebocyte Biology

We have previously shown that endocannabinoids (eCBs) (e.g., anandamide) are involved in the maintenance of homeostatic sebaceous lipid production in human sebaceous glands and that eCB treatment dramatically increases sebaceous lipid production. Here, we aimed to investigate the expression of the major eCB synthesizing and degrading enzymes and to study the effects of eCB uptake inhibitors on human SZ95 sebocytes, thus exploring the role of the putative eCB membrane transporter, which has been hypothesized to facilitate the cellular uptake and subsequent degradation of eCBs. We found that the major eCB synthesizing (N-acyl phosphatidylethanolamine-specific phospholipase D, and diacylglycerol lipase-α and -β) and degrading (fatty acid amide hydrolase, monoacylglycerol lipase) enzymes are expressed in SZ95 sebocytes and also in sebaceous glands (except for diacylglycerol lipase-α, the staining of which was dubious in histological preparations). eCB uptake-inhibition with VDM11 induced a moderate increase in sebaceous lipid production and also elevated the levels of various eCBs and related acylethanolamides. Finally, we found that VDM11 was able to interfere with the proinflammatory action of the TLR4 activator lipopolysaccharide. Collectively, our data suggest that inhibition of eCB uptake exerts anti-inflammatory actions and elevates both sebaceous lipid production and eCB levels; thus, these inhibitors might be beneficial in cutaneous inflammatory conditions accompanied by dry skin.

Sebocytes contribute to skin inflammation by promoting the differentiation of T helper 17 cells.

The main function of sebocytes is considered to be the production of lipids to moisturize the skin. However, it recently became apparent that sebocytes release chemokines and cytokines and respond to proinflammatory stimuli as well as the presence of bacteria. To analyse the functional communication between human sebocytes and T cells. Immunofluorescence stainings for CD4 and interleukin (IL)-17 were performed on acne sections and healthy skin. Migration assays and T-cell-stimulation cultures were performed with supernatants derived from unstimulated or prestimulated SZ95 sebocytes. Dendritic cells were generated in the presence of SZ95 supernatant and subsequently used in mixed leucocyte reactions. We showed that CD4+ IL-17+ T cells accumulate around the pilosebaceous unit and are in close contact with sebocytes in acne lesions. By using SZ95 sebocyte supernatant, we demonstrate a chemotactic effect of sebocytes on neutrophils, monocytes and T cells in a CXCL8-dependent manner. Furthermore, sebocyte supernatant induces the differentiation of CD4+ CD45RA+ naive T cells into T helper (Th)17 cells via the secretion of IL-6, transforming growth factor-β and, most importantly, IL-1β. No direct effects of sebocytes on the function of CD4+ CD45RO+ memory T cells were detected. Moreover, sebocytes functionally interact with Propionibacterium acnes in the maturation of dendritic cells, leading to antigen-presenting cells that preferentially prime Th17 cells. Our study provides evidence that human sebocytes actively participate in inflammatory processes in the skin by recruiting and communicating with immune cells. This interaction leads to the generation of Th17 cells, which might contribute to the pathogenesis not only of acne vulgaris, but also of several inflammatory skin diseases.

Sebum lipids influence macrophage polarization and activation.

As lipids are known to regulate macrophage functions, it is reasonable to suppose that a sebocyte-macrophage axis mediated by sebum lipids may exist. To investigate if sebocytes could contribute to the differentiation, polarization and function of macrophages with their secreted lipids. Oil Red O lipid staining and Raman spectroscopy were used to assess the dermal lipid content and penetration. Immunohistochemistry was used to analyse the macrophage subsets. Human peripheral blood monocytes were differentiated in the presence of either supernatant from human SZ95 sebocytes or major sebum lipid components and activated with Propionibacterium acnes. Macrophage surface markers and their capacity to uptake fluorescein isothiocyanate-conjugated P.acnes were detected by fluorescence-activated cell sorting measurements. Cytokine protein levels were evaluated by enzyme-linked immunosorbent assay and Western blot analysis. Sebaceous gland-rich skin had an increased dermal lipid content vs. sebaceous gland-poor skin to which all the tested sebum component lipids could contribute by penetrating the dermoepidermal barrier. Of the lipids, oleic acid and linoleic acid promoted monocyte differentiation into alternatively activated macrophages. Moreover, linoleic acid also had an anti-inflammatory effect in P.acnes-activated macrophages, inhibiting the secretion of interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)-α. Squalene, palmitic acid, stearic acid and oleic acid augmented the secretion of IL-1β, even in the absence of P. acnes, whereas oleic acid had a selective effect of inducing IL-1β but downregulating IL-6 and TNF-α secretion. Our results suggest a role for sebaceous glands in modulating innate immune responses via their secreted lipids that are of possible pathological and therapeutic relevance.

OLR1 scavenger receptor knockdown affects mitotic gene expression but is dispensable for oxidized phospholipid- mediated stress signaling in SZ 95 sebocytes

Phospholipid oxidation products (OxPL) are versatile stress signaling mediators in the skin. These lipid signaling molecules can be generated non-enzymatically or enzymatically by ultraviolet light, the major extrinsic skin aging factor. OxPL regulate cytoprotective, immunological and metabolic adaptation of the skin to oxidant stress. We here investigated whether the scavenger receptor Oxidized Low Density Lipoprotein Receptor 1 (OLR1, LOX-1) would have a function in cutaneous oxPL signaling. We found, that OLR1 is expressed in several cutaneous cell types, most prominently in cells of the sebaceous gland and in keratinocytes. We repressed OLR1 expression with siRNA in SZ95 sebocytes, exposed cells to oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (PAPC) and performed transcriptomic profiling. Bioinformatic analysis revealed that OxPL exposure induced the Nrf2 antioxidant stress response and aldosterone signaling. The analysis also revealed that OLR1 is not required for the transcriptional regulation induced by oxidized PAPC but interestingly, OLR1 knockdown affected expression of CNN2, HMRR, ITGB6 and KIF20A, all genes governing cell proliferation and motility. We identify sebocytes as cutaneous cells responsive to lipid mediated redox stress which is not dependent on the scavenger receptor OLR1.

Particulate matter 2.5 regulates lipid synthesis and inflammatory cytokine production in human SZ95 sebocytes.

A large body of evidence indicates that particulate matter (PM)2.5 is associated with various negative effects on human health. However, the impact and molecular mechanism of PM2.5 on the skin have not been elucidated. Therefore, the present study aimed to investigate the effects of two types of PM2.5 [water-soluble extracts (W-PM2.5) and non-water-soluble extracts (NW-PM2.5)] on cell proliferation, cell cycle progression, lipid synthesis, and inflammatory cytokine production of human SZ95 sebocytes. The results demonstrated that NW-PM2.5 and W-PM2.5 exposure dose-dependently inhibited SZ95 sebocyte proliferation by inducing G1 cell arrest. Furthermore, NW-PM2.5 and W-PM2.5 significantly reduced sebaceous lipid synthesis and markedly promoted the production of inflammatory cytokines, including interleukin-1α (IL-1α), IL-6 and IL-8 in SZ95 sebocytes. Additionally, the expression of aryl hydrocarbon (Ah) receptor (AhR), AhR nuclear translocator protein (ARNT), as well as cytochrome P450 1A1 were significantly increased following PM2.5 exposure. Thus, these findings indicate that PM2.5 exerts inhibitory effects on cell proliferation and lipid synthesis, and stimulatory effects on inflammatory cytokine production and AhR signaling activation in human SZ95 sebocytes.

ALA-PDT suppressing the cell growth and reducing the lipogenesis in human SZ95 sebocytes by mTOR signaling pathway in vitro

Background5-Aminolevulinic acid mediated −photodynamic therapy (ALA-PDT) is known to be effective in treating acne vulgaris and other sebaceous gland-related diseases. However, the therapeutic mechanisms of ALA-PDT still remain undetermined. In this study, we aimed to investigate the effects and mechanisms of ALA-PDT on the cell growth and lipogenesis of human SZ95 sebocytes. Material and methodsHuman SZ95 sebocytes were treated with different concentration of ALA-PDT.CCK-8 assay was used to detect cell proliferation activity. Fluorescence microscope and flow cytometry were used to observe the secretion of lipids in SZ95 cells after Nile red staining. Western blotting was used to detect and analyze the protein expression level of P-p70 S6K/p70 S6K, P-4E-BP1/4E-BP1, SREBP-1, PPARγ, P-mTOR/mTOR, and P-Raptor/Raptor. Mean while, mTOR pathway activator IGF-1 and mTORC1 inhibitor rapamycin were added to observe the interferences on the ALA-PDT treatment of SZ95 cells. ResultsALA-PDT suppressed the cell growth and reduced the secretion of lipids in a dose-dependent manner in SZ95 cells. ALA-PDT reduced the protein levels of P-p70 S6K (T389), SREBP-1, PPARγ, P-mTOR and P-Raptor. IGF-1 had counter effects on ALA-PDT, and rapamycin enhanced the effects of ALA-PDT in SZ95 cells in suppressing the cell growth and reducing the secretion of lipids. ConclusionALA-PDT suppressed the cell growth in SZ95 cells by mTOR-p70 S6K(T389) signaling and reduced the lipogenesis in SZ95 cells by mTOR-SREBP-1/PPARγ signaling. Sebaceous glands atrophy and reduction of sebum secretion after ALA-PDT may be caused by the suppression of lipogenesis and cell growth in sebocytes.

ALA-PDT effect on the biological characteristics of human SZ95 sebocytes

ALA-PDT effect on the biological characteristics of human SZ95 sebocytes

Effects of Isotretinoin on the Phosphoinositide-3-kinase/Akt/FoxO1 Pathway and Molecular Functions of SZ95 Sebocytes In vitro

Objective: For more than 3 decades, isotretinoin [13-cis retinoic acid (13-cis RA)] is established as the most potent oral treatment for severe acne. However, the molecular mechanisms of isotretinoin action have not been fully elucidated. Recently, we showed that insulin and insulin-like growth factor 1 (IGF-1) increase differentiation and decrease proliferation of SZ95 sebocytes in vitro via activation of the phosphoinositide 3-kinase (PI3K)/Akt/forkhead box-O1 (FoxO1) pathway. Furthermore, this pathway is activated in patient acne biopsies in vivo. Using SZ95 sebocytes as an in vitro model, the aim of this study was to investigate the effect of isotretinoin on PI3K pathway activation. Methods: SZ95 sebocytes were treated under light protection with 0.1 μM isotretinoin in the presence or absence of 1.0 and 0.1 μM IGF-1 or insulin or 50 μM LY294002 inhibitor in a time- dependent manner. The expression of p-Akt and its downstream target p-FoxO1 was analyzed by Western blot. FoxO transcriptional activity was measured by dual luciferase assay. Nuclear and cytoplasmic mobilization of FoxO1, p-FoxO1, and p-Akt were also determined by immunofluorescence microscopy.Proliferation of sebocytes was measured by [3H]-thymidine incorporation and sebocyte differentiation by oil red O staining. Results: We show that isotretinoin activates the PI3K/Akt pathway and decreases the nuclear content of FoxO1 and its transcriptional activity in sebocytes in vitro and in sebaceous gland biopsies from an isotretinoin-treated acne patient. Isotretinoin reduces the proliferation of IGF-1- or insulin-stimulated sebocytes more effectively than IGF-1 and insulin alone. However, it normalizes the increased lipid accumulation in IGF-1- or insulin-stimulated sebocytes via a PI3K-independent pathway. Conclusion: Our data from the SZ95 sebocyte in vitro model suggest that the potent therapeutic effect of isotretinoin in acne is not mediated via the PI3K/Akt/FoxO1 pathway.

Effects of Extracellular Calcium and 1,25 dihydroxyvitamin D3 on Sebaceous Gland Cells In vitro and In vivo

Calcium and 1,25 dihydroxyvitamin D3 (1,25(OH)2D3) are promoters of epithelial cell functions; however their effects on sebaceous glands are unknown. In this study, morphology, ultrastructure, cell numbers, lipid synthesis and apoptosis of SZ95 sebocytes were assessed in vitro under different concentrations of extracellular calcium with or without 1,25(OH)2D3. Moreover, serum calcium and 1,25(OH)2D3 levels were assessed in acne and non-acne patients (controls). Under conditions of low extracellular calcium, lipogenesis and cell detachment were observed. Increasing extracellular calcium enhanced sebocyte numbers, induced epithelial morphology and reduced lipogenesis. Moreover, a reduction in extracellular calcium reduced E-cadherin and enhanced caspase 3/7 activity (apoptosis), whereas calcium chelation by EGTA (ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid) resulted in enhanced lipogenesis. 1,25(OH)2D3 decreased sebaceous lipogenesis, but also induced signs of autophagy. In the clinical study, patients and controls exhibited normal serum calcium levels. Younger acne patients presented lower 1,25(OH)2D3 levels than did older ones. In conclusion, extracellular calcium and 1,25(OH)2D3 regulate sebocyte morphology, increase cell numbers, decrease sebaceous lipogenesis and induce cell autophagy in vitro. The increased ionized calcium and the reduced 1,25(OH)2D3 levels detected in the serum of younger patients with acne may contribute respectively to increased sebaceous gland volume and enhanced lipogenesis.

Insulin and Insulin-like growth factor-1 can activate the phosphoinositide-3-kinase /Akt/FoxO1 pathway in T cells in vitro.

ABSTRACTHyper-glycemic food increases insulin-like growth factor 1 (IGF-1) and insulin signaling and regulates endocrine responses and thereby may modulate the course of acne. Inflammation and adaptive immune responses have a pivotal role in all stages of acne. Recent hypothesis suggests that hyperglycemic food reduces nuclear forkhead box-O1 (FoxO1) transcription factor and may eventually induces acne. The aim of our study was to investigate the role of IGF-1 and insulin on the phosphoinositide-3-kinase (PI3K)/Akt/FoxO1 pathway in human primary T cells and on the molecular functions of T cells in vitro. T cells were stimulated with 0.001 μM IGF-1 or 1 μM insulin +/− 20 μM PI3K inhibitor LY294002. T cells were also exposed to SZ95 sebocyte supernatants which were pre-stimulated with IGF-1 or insulin. We found that 0.001 µM IGF-1 and 1 µM insulin activate the PI3K pathway in T cells leading to up-regulation of p-Akt and p-FoxO1 at 15 and 30 minutes. Nuclear FoxO1 was decreased and FoxO transcriptional activity was reduced. 0.001 µM IGF-1 and 1 µM insulin increased T cell proliferation but have no significant effect on Toll-like receptor2/4 (TLR) expression. Interestingly, supernatants from IGF-1- or insulin-stimulated sebocytes activated the PI3K pathway in T cells but reduced T cell proliferation. Taken together, this study helps to support that high glycemic load diet may contribute to induce activation of the PI3K pathway and increase of proliferation in human primary T cells. Factors secreted by IGF-1- and insulin-stimulated sebocytes induce the PI3K pathway in T cells and reduce T cell proliferation, which probably can reflect a protective mechanism of the sebaceous gland basal cells.

Pro-inflammatory sebocyte growth and survival signalling in acne vulgaris are reversed by pro-apoptotic isotretinoin signalling.

Pro-inflammatory sebocyte growth and survival signalling in acne vulgaris are reversed by pro-apoptotic isotretinoin signalling.

Aryl hydrocarbon receptor negatively regulates lipid synthesis and involves in cell differentiation of SZ95 sebocytes in vitro

The aryl hydrocarbon receptor (AhR) is the receptor for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), benzo(a)pyrene (BaP) and other exogenous compounds. In human sebocytes, TCDD and BaP were found to activate the expression of multiple genes, including cytochrome P450 1A1 (CYP1A1), and inhibit lipid synthesis via AhR, while little is known about endogenous functions of the AhR. In order to expand this knowledge, we analyzed the impact of AhR knockdown on lipid synthesis as well as on cell differentiation of SZ95 sebocytes in vitro and observed that lipid synthesis was significantly induced in AhR silenced SZ95 sebocytes. In line with this result, expression of lipogenesis-associated genes, such as peroxisome proliferator activated receptor (PPAR) δ and PPARγ, was increased. Morphological changes with smaller cells in size but more abundant cytoplasmic lipids were observed in AhR silenced SZ95 sebocytes compared with the AhR activated cells. Besides, the expression of keratin 7, an early sebaceous differentiation marker, was increased, while the expression of the terminal sebocyte differentiation marker epithelial membrane antigen (EMA) was reduced. Moreover, the terminal keratinocyte differentiation markers keratin 10 and involucrin, and the AhR downstream protein CYP1A1 were reduced after AhR silencing. To the best of our knowledge, we provide evidence that in the absence of exogenous ligands, the AhR inhibits lipid synthesis and involves in cell differentiation of human SZ95 sebocytes, which indicates the physiological function of this receptor in human sebocytes.