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Propionibacterium acnes is considered to be involved in the aggravation of acne vulgaris, but it remains unclear whether P. acnes directly influences lipogenesis in sebaceous glands. In this study, we showed that a culture medium of P. acnes (acnes-CM) and formalin-killed P. acnes (F-acnes) prepared from P. acnes strains, JCM6473 and JCM6425, intracellularly augmented lipid droplet formation and triacylglycerol (TG) synthesis in undifferentiated and insulin-differentiated hamster sebocytes. Acnes-CM and F-acnes prepared from four clinical P. acnes strains elicited the same lipogenesis augmentation. The augmented TG production resulted from an increase in the diacylglycerol acyltransferase activity. Topical application of acnes-CM to the skin of hamster auricles every day for 4 weeks revealed that sebum accumulation was augmented in sebaceous glands and ducts. Furthermore, both acnes-CM and F-acnes increased the production of 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), a cytochrome P450 (CYP)-linked sebaceous lipogenic factor, in differentiated sebocytes. A CYP inhibitor, SKF-525A, decreased the acnes-CM- and F-acnes-augmented production of TG and 15d-PGJ(2). Thus, to our knowledge these results provide previously unreported evidence that P. acnes directly participates in the augmentation of sebaceous lipogenesis through a proposed mechanism in which an increase of 15d-PGJ(2) production through the CYP pathway is closely associated with the enhancement of TG production.

In this issue, Iinuma et al. show that Propionibacterium acnes (P. acnes)-conditioned medium and formalin-killed P. acnes augment intracellular lipid formation in hamster sebocytes by increasing the de novo synthesis of triacylglycerols. This commentary summarizes the current knowledge of the association of P. acnes with sebaceous lipogenesis, inflammation, and innate immunity, and points out the concurrent evidence that P. acnes-induced lipids may represent a recruitment of allies and/or enemies of the human skin.

A cross-sectional, community-based study was performed to determine the prevalence and severity of acne vulgaris in adolescents and of factors influencing the acne severity risk. The presence of acne was clinically determined and the secondary outcome measures of family acne history and the relation of acne to nutrition habits, emotional stress, menstruation, and smoking were recorded in a questionnaire. A representative sample of 1,002 pupils aged 16+/-0.9 years was enrolled. The overall acne prevalence was 93.3, 94.4% for boys and 92.0% for girls. Moderate to severe acne was observed in 14%. The prevalence of moderate to severe acne was 19.9% in pupils with and 9.8% in those without a family history of acne (P<0.0005; OR: 2.3). Acne severity risk increased with the number of family members with acne history. A mother with acne history influenced the severity of acne the most. Increasing pubertal age, seborrhea, the premenstrual phase, mental stress, and sweet and oily foods were recognized as risk factors for moderate to severe acne. In contrast, gender, spicy foods, and smoking were not associated with acne severity. In conclusion, acne is a common disorder in Iranian adolescents, with a low rate of moderate to severe acne. A genetic background is suggested, with mother's acne history being the most important prognostic factor. Skin quality and certain nutrition habits may affect acne severity.

Increased fibroblast growth factor receptor-2 (FGFR2) signaling has been proposed to be involved in acne pathogenesis and explains acne lesions in Apert syndrome and unilateral acneiform nevus associated with gain-of-function point mutations of FGFR2. If, indeed, increased FGFR2 signaling plays a major pathogenic role in follicular hyperkeratinization and sebaceous gland hypertrophy in acne, effective anti-acne drugs may attenuate increased FGFR2 signaling. The purpose of this article is to elucidate the hypothesis that known anti-acne agents may operate by downregulation of increased FGFR2 signaling. Anti-androgens suppress FGF-ligand expression, benzoyl peroxide induces FGFR2 downregulation by lysosomal receptor degradation, azelaic acid inhibits mitochondrial ATP formation required for receptor tyrosine kinase phosphorylation, tetracyclines inhibit the expression, and activity of FGFR2b downstream matrix metalloproteinases, and retinoids attenuate the FGFR2 pathway at several regulatory levels of the signal transduction cascade critical for cell cycle control, cell proliferation, differentiation, and lipogenesis. Erythromycin, a P-450 inhibitor, may interfere with FGFR2 signaling by its inhibitory effect on retinoid catabolism. The gain-of-function mutations of FGFR2 in Apert syndrome and unilateral acneiform nevus, and the proposed synergistic inhibitory interactions of anti-acne agents at various levels of the FGFR2-signaling cascade underline the role of FGFR2 signaling in the pathogenesis of acne.

Acne is a chronic disease hallmarked by sebaceous hyperplasia, follicular hyperkeratosis, and inflammation. Parallel targeting of these factors is required to treat acne effectively. Inhibitors of dipeptidyl peptidase IV (DP IV) and aminopeptidase N (APN) show strong anti-inflammatory effects on immune cells and therapeutic efficacy in autoimmune disorders. Our investigation focused on the expression and functional relevance of these ectopeptidases in three cell types which exhibit an altered phenotype in early acne lesions. We showed for the first time expression of DP IV and APN on human sebocytes. In the SZ95 sebocyte cell line, the DP IV inhibitors Lys[Z(NO2)]-thiazolidide and Lys[Z(NO2)]-pyrrolidide and the APN inhibitors actinonin and bestatin suppressed proliferation, enhanced terminal differentiation, and slightly decreased total neutral lipid production. The anti-inflammatory and differentiation-restoring cytokine IL-1 receptor antagonist was significantly upregulated in SZ95 sebocytes and the HaCaT keratinocyte cell line in the presence of inhibitors. Furthermore, the inhibitors suppressed proliferation and IL-2 production of Propionibacterium acnes-stimulated T cells ex vivo and enhanced the expression of the immunosuppressive cytokine transforming growth factor-beta1. Our data provide first evidence for a functional role of DP IV and APN in the sebaceous gland apparatus and for their inhibitors, used alone or in combination, as completely new substances possibly affecting acne pathogenesis in a therapeutic manner.

In order to investigate whether products derived from the oxidation of sebum can be responsible for the induction of inflammatory processes, HaCaT keratinocytes were treated with peroxidated squalene. NF-kappaB activation, secretion, and expression of IL-6, as well as peroxisome proliferator-activated receptor alpha (PPARalpha) mRNA and protein levels, were measured at the end of the treatment and after 24 and 48 hours of recovery. Squalene peroxidation products were administered in amounts able to elicit significant hyperproliferation and to induce lipoxygenase (LOX) activity. The results showed an early activation of NF-kappaB followed by an increase in PPARalpha mRNA and protein levels. Moreover, squalene peroxides induced an initial upregulation of IL-6 production and secretion that was counteracted by PPARalpha activation, as suggested by the subsequent decrease of NF-kappaB nuclear translocation and IL-6 levels. Inflammatory processes play an important role in the development of acne vulgaris. In combination with our own previous findings, which indicated an association between LOX stimulation and increased percentage of proinflammatory lipids in acne as well as a correlation between increased cytokine levels in the infundibulum, pilosebaceous duct hyperkeratinization, and augmented sebogenesis, the present data further support the involvement of lipid peroxides, in particular squalene peroxides, in establishing an inflammatory process in acne.

Acne vulgaris is a skin disorder of the sebaceous follicles, involving hyperkeratinization and perifollicular inflammation. Matrix metalloproteinases (MMP) have a predominant role in inflammatory matrix remodeling and hyperproliferative skin disorders. We investigated the expression of MMP and tissue inhibitors of MMP (TIMP) in facial sebum specimens from acne patients, before and after treatment with isotretinoin. Gelatin zymography and Western-blot analysis revealed that sebum contains proMMP-9, which was decreased following per os or topical treatment with isotretinoin and in parallel to the clinical improvement of acne. Sebum also contains MMP-1, MMP-13, TIMP-1, and TIMP-2, as assessed by ELISA and western blot, but only MMP-13 was decreased following treatment with isotretinoin. The origin of MMP and TIMP in sebum is attributed to keratinocytes and sebocytes, since we found that HaCaT keratinocytes in culture secrete proMMP-2, proMMP-9, MMP-1, MMP-13, TIMP-1, and TIMP-2. SZ95 sebocytes in culture secreted proMMP-2 and proMMP-9, which was also confirmed by microarray analysis. Isotretinoin inhibited the arachidonic acid-induced secretion and mRNA expression of proMMP-2 and -9 in both cell types and of MMP-13 in HaCaT keratinocytes. These data indicate that MMP and TIMP of epithelial origin may be involved in acne pathogenesis, and that isotretinoin-induced reduction in MMP-9 and -13 may contribute to the therapeutic effects of the agent in acne.

Abnormal follicular keratinization is involved in comedogenesis in acne vulgaris. We recently demonstrated that calcium influx into epidermal keratinocytes is associated with impaired skin barrier function and epidermal proliferation. Based on these results, we hypothesized that sebum components affect calcium dynamics in the keratinocyte and consequently induce abnormal keratinization. To test this idea, we first observed the effects of topical application of sebum components, triglycerides (triolein), saturated fatty acids (palmitic acid and stearic acid), and unsaturated fatty acids (oleic acid and palmitoleic acid) on hairless mouse skin. Neither triglyceride nor saturated fatty acids affected the skin surface morphology or epidermal proliferation. On the other hand, application of unsaturated fatty acids, oleic acid, and palmitoleic acid induced scaly skin, abnormal keratinization, and epidermal hyperplasia. Application of triglycerides and saturated fatty acids on cultured human keratinocytes did not affect the intracellular calcium concentration ([Ca(2+)](i)), whereas unsaturated fatty acids increased the [Ca(2+)](i) of the keratinocytes. Moreover, application of oleic acid on hairless mouse skin induced an abnormal calcium distribution in the epidermis. These results suggest that unsaturated fatty acids in sebum alter the calcium dynamics in epidermal keratinocytes and induce abnormal follicular keratinization.

Acne is common and often leads to significant psychologic and physical morbidity. From clinical experience, acne appears to run in families; however, very few studies have investigated the genetic basis of this very common skin disease. A large twin study based on 458 pairs of monozygotic and 1099 pairs of dizygotic twins, all women with a mean age of 46 y was performed to investigate the relative contribution of genetic and environmental factors on the liability to acne. In addition, potential risk factors were assessed in twins with and without acne in a nested cross-sectional design. Fourteen percent of the twins reported a history of acne. Genetic modeling using acne scores showed that 81% (95% confidence interval 73-87%) of the variance of the disease was attributable to additive genetic effects. The remaining 19% was attributed to unique (i.e., unshared) environmental factors. Of the potential risk factors tested in 400 acne twins and 2414 unaffected twins, only apolipoprotein A1 serum levels were significantly lower in acne twins even after adjusting for age and weight. Family history of acne was also significantly associated with an increased risk. No significant differences were found between acne twins and nonacne twins for weight, body mass index, height, birth weight, hair thinning, reproductive factors as well as cholesterol, triglycerides, high-density lipoprotein, and glucose levels. The lower serum levels of apolipoprotein A1 in acne twins were also confirmed when analyzing acne discordant twin pairs. The evidence of a major genetic influence on acne should stimulate the search for potential genes that may lead to new therapeutic approaches.

Comedonal lipids and skin surface lipids were collected from six acne patients and surface lipids were collected from sex- and age-matched controls without acne. Six series of ceramides were found in each sample, the relative amounts of which were determined by thin-layer chromatography/photodensitometry. Acylceramides (ceramide 1) were isolated by preparative thin-layer chromatography and their ester-linked fatty acids were analyzed by gas-liquid chromatography. The comedonal acylceramides contained higher proportions of 16:0, 16:1 delta 6, and 18:1 delta 6 + delta 8 and much less linoleate (18:2 delta 9,12) than the acylceramides from the skin surface. In the surface lipids from legs, acylceramides from the acne patients contained less linoleate than the acylceramides from control subjects. Free fatty acids from the comedones were also isolated and analyzed, and had a composition very similar to the esterified fatty acids of comedonal acylceramides. The results confirm that fatty acids derived from sebum become incorporated into comedonal acylceramides, displacing linoleate, and show that this process even affects the acylceramides of surface epidermis, more so in acne patients than in normal subjects.

Sebaceous wax esters and epidermal acylceramides were isolated from skin surface lipid obtained from children and from young adults. Fatty acid methyl esters (FAME) were prepared from the esterified fatty acids of these lipid classes and analyzed to ascertain the proportions of methyl linoleate (18:2 delta 9,12), methyl sebaleate (18:2 delta 5,8), and methyl sapienate (16:1 delta 6). On the same subjects, 2 measures of sebum secretion rate were obtained, namely the sustainable wax ester secretion rate (WESR) on the forehead and the ratio of wax esters/(cholesterol + cholesterol esters) [WE/(CH + CE)] in the surface lipid. The proportions of methyl linoleate in FAME from the wax esters decreased, and the proportions of methyl sebaleate increased, with increased rates of sebum secretion. For both methyl linoleate and methyl sebaleate, a better correlation was obtained when the ratio of WE/(CH + CE) was used as a measure of sebum secretion rather than the WESR. The proportions of methyl linoleate in the FAME from the acylceramides were also inversely related to ratios of WE/(CH + CE). In acylceramides, linoleate was replaced by sapienate, a major fatty acid of human sebum. It appears, therefore, that sebum fatty acid composition may change with changes in sebaceous gland activity, and that sebum fatty acids can enter the epidermis and be incorporated into epidermal lipids.

No mycoplasmas and no chlamydiae were found in cultures of 75 uninflamed comedones, 72 papulopustular lesions, and 7 cystic lesions from 14 subjects with acne. Chlamydial serologic tests were negative for 11 subjects and showed antibodies in 3 subjects to 3 different antigenic types of trachoma agent. These results are viewed as substantial evidence against the possibility that either mycoplasmas or chlamydiae play an important part in the pathogenesis of acne.