Dermato-Endocrinology 3:1, 41-49; January/February/March 2011; © 2011 Landes Bioscience
`
`REVIEW
`
`An update on the role of the sebaceous gland
`in the pathogenesis of acne
`
`Evgenia Makrantonaki,1,2 Ruta Ganceviciene3 and Christos Zouboulis1·*
`
`'Departments of Dermatology, Venereology, Allergology and Immunology; Dess au Medic a I Center; Dessa u, Germany; ' Laboratory for Blogerontology;
`Derma to-Pharmacology and Derma to-Endocrinology; Institute of Clinical Pharmacology and Toxicology; Charlte Unlversltaetsmedlzln Berl In; Berlin, Germany;
`'Centre of Dermatovenereology; VIinius University Hospital Santarlsklu kllnlkos; Vllnlu s, Lithuania
`
`Keywords: sebaceous gland cells, acne, hormones, stress, inflammation, propionebacterium acnes
`
`Abbreviations: AA, arachidonic acid; ACTH, adrenocorticotropine hormone; AMPs, antimicrobial peptides; AR,
`androgen receptor; COX, cycloxygenase; CR, cannabinoid receptor; CRH, corticotropin-releasing hormone; DHEAS,
`dehydroepiandrosterone sulphate; 5a-DHT, 5a-dihydrostestosterone; DPH, diphenhydramine; GH, growth hormone;
`H -1 receptor, histamine-I receptor; hBDs, human ~ -defensins; IGF-1, insulin growth factor-I; LXR, liver-X receptor; LOX,
`lipoxygenase; LT, leucotrienes; a -MSH, a -melanocyte-stimulating hormone; MMPs, matrix metalloproteinases; MC,
`melanocortin; MUFAs, monounsaturated fatty acid; NP, neuropeptide; PG, prostaglandins; P, acnes, Propionibacterium acnes;
`POMC, propiomelanocortin; PPAR, peroxisome proliferator-activated receptor; RA, retinoic acid; RAR, retinoid acid receptor;
`RXR, retinoid X receptor; SCD, stearoyl coenzyme A; SREBP-1, sterol response element-binding protein-I; TLRs, toll-like
`receptors; TNFa, tumor necrosis factora; TRPVl, transient receptor potential vanilloid-1; VDR, vitamin D receptor
`
`The pathogenesis of acne, a disease of the pilosebaceous
`follicle and one of the most common chronic skin disorders,
`is attributed to multiple factors such as increased sebum
`lipids,
`production, alteration of the quality of sebum
`inflammatory processes, dysregulation of the hormone
`microenvironment, interaction with neuropeptides, follicular
`hyperkeratinisation and the proliferation of Propionibacterium
`acnes within the follicle. In particular, the sebaceous gland
`plays an exquisite role in the initiation of the disease as it
`possesses all the enzyme machinery for the production of
`hormones and cytokines. In addition, in response to the
`altered tissue environment in the pilosebaceous follicle as
`well as in answer to emotional fret, stress response system
`mechanisms with induction of central and local expression of
`neuropeptides, are also initiated. This review summarises the
`latest advances in understanding the role of sebaceous gland
`cells in the pathomechanism of acne.
`
`Introduction
`
`Sebaceous glands are holocrine glands found over the entire sur(cid:173)
`face of the body except the palms, soles and dorsum of the feet.
`They are largest and most concentrated in the face and scalp
`where they are the sites of origin of acne (Fig. 1). The normal
`function of sebaceous glands is to produce and secrete sebum,
`a group of complex oils including triglycerides and fatty acid
`breakdown products, wax esters, squalene, cholesterol esters and
`
`*Correspondence to: Christos C. Zoubou 11s;
`Email: chrlstos.zouboulls@kllnlkum-dessau.de
`Submitted: 09/24/10; Accepted: 10/05/10
`DOI: 10.4161/derm.3.1.13900
`
`cholesteroI. 1- 4 Schum lubricates the skin to protect against fric(cid:173)
`tion and makes it more impervious to moisture. Furthermore, the
`sebaceous gland transports antioxidants in and on the skin and
`exhibits a natural light protective activity. It possesses an innate
`antibacterial activity and has a pro- and anti-inflammatory func(cid:173)
`tion. It can regulate the activity of xenobiotics and is actively
`involved in the wound healing process.5
`In the last years, acne research has made a remarkable progress
`in understanding the mechanisms involved in the pathogenesis
`of the disease by using cell culture models and new molecular
`techniques. Mammal sebocytes and sebocyte-like cells (human,
`mouse, hamster and rat) and human sebaceous gland cell lines
`(SZ95, SEB-1, Seb-E6E7) 6•8 have been used in monolayer cul(cid:173)
`tures as models to study specific functions involved in develop(cid:173)
`ment, growth and differentiation of sebaceous gland cells. More
`complex culture systems, including three-dimensional models,
`are under development.
`
`Sebum and Acne
`
`Increased sebum excretion, alteration oflipid composition and the
`oxidant/antioxidant ratio characteristic of the skin surface lipids
`are major concurrent events associated with the development of
`acne.5 If sebum interferes with the process of follicular keratinisa(cid:173)
`tion in the pilosebaceous unit, pore blockage may occur, contrib(cid:173)
`uting to lesion formation and acne. However, seborrhoea per se is
`not considered to be the only responsible factor for the develop(cid:173)
`ment of acne, as demonstrated by the success of treatment with
`agents with no effect on sebum secretion rate that can inhibit
`the inflammatory process, such as antibiotics, topical retinoids,
`azelaic acid and benzoyl peroxide.9 The composition of the pro(cid:173)
`duced lipids is also of great importance. Lower essential fatty acid
`levels were found in wax esters in twins with acne rather than in
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`Figure 1. Pilosebaceous unit in facial skin of acne patients. Faintly hypertrophic sebaceous gland are observed. Dilated capillaries and perivascular
`lymphocytes (A and C) are early signs of inflammatory process in acne-involved skin. Dilated plugged orifice of hair follicle—sign of acne comedo (B).
`
`twins with no acne.10 Moreover, low levels of linoleic acid have
`been observed in skin surface lipids of acne patients.11 Evidence
`suggests that diet may be an important source of substrate for
`the synthesis of sebaceous lipids.12 This notion is supported also
`by the observation that sebum contains linoleic acid, an essential
`fatty acid that cannot be synthesised in vivo and therefore must
`be obtained from the diet. It has recently been hypothesised that
`low glycemic load diet may influence sebum production based on
`the beneficial endocrine effects of its components.13
`On the other hand, extreme caloric restriction dramatically
`decreases the sebum excretion rate and these changes can be
`reversed when a normal diet is resumed.14,15 Other studies have
`demonstrated that increased consumption of dietary fat or car-
`bohydrate increases sebum production and modifications to the
`type of carbohydrate can also alter sebum composition.16 Typical
`western diet, comprised of milk and hyperglycaemic foods,
`may have potentiating effects on serum insulin and insulin-like
`growth factor-I (IGF-I) levels, thereby promoting the develop-
`ment of acne.17
`Another hallmark of sebum in acne patients is the presence of
`lipoperoxides, mainly due to the peroxidation of squalene and a
`decrease in the level of vitamin E, the major sebum antioxidant.18
`Both lipoperoxides and monounsaturated fatty acid (MUFA) are
`capable of inducing alteration in keratinocyte proliferation and
`differentiation, whereas peroxides are capable of inducing pro-
`duction of pro-inflammatory cytokines and activation of peroxi-
`some proliferator-activated receptors (PPAR).13,18
`The biological function of sebocytes is further regulated
`by several factors including ligands of receptors expressed in
`sebocytes, such as androgens and estrogens, PPAR ligands and
`neuropeptides (NP), liver-X receptor ligands (LXR), hista-
`mines, retinoids and vitamin D. The ligand-receptor complexes
`activate pathways involving cell proliferation, differentiation,
`lipogenesis, hormone metabolism and cytokine and chemokine
`release19 (Fig. 2).
`
`LXR, which are members of the nuclear receptor superfamily,
`and play a critical role in cholesterol homeostasis and lipid metab-
`olism have been documented to regulate lipid synthesis in the
`immortalised human sebaceous gland cell line SZ95. Treatment
`of SZ95 sebocytes with LXR ligands such as TO901317 or
`22(R)-hydroxycholesterol, enhanced accumulation of lipid drop-
`lets in the cells which could be explained through induction of
`the expression of the LXRalpha receptor and known LXR tar-
`gets, such as fatty acid synthase and sterol regulatory-binding
`protein-1.20,21
`On the other hand, sebaceous function can be also signifi-
`cantly modified by histamine and conversely, antihistamines.
`Diphenhydramine (DPH), a histamine 1 receptor antagonist,
`significantly decreases squalene levels in human sebaceous gland
`cells as determined by means of high-performance liquid chro-
`matography. These data were further verified by the identifica-
`tion of histamine 1 receptor in human sebaceous glands.22
`Retinoids are also suggested to influence the biological func-
`tion of sebocytes. Retinoic acid receptors (RAR; isotypes α and
`γ) and retinoid X receptors (RXR; isotypes α, β, γ) are expressed
`in human sebocytes.23 The natural ligands for RAR and RXR are
`all-trans (atRA) and 9-cis retinoic acid (9cRA). In SZ95 sebo-
`cytes 13-cis retinoic acid (13cRA) may unfold its action through
`a marked isomerisation to atRA. All three isoforms atRA, 13cRA
`and 9cRA exhibit anti-proliferative effects24 and inhibit sebocyte
`differentiation and lipid synthesis.25 RXR agonists stimulate
`sebocyte differentiation and proliferation. The RXR agonist
`rexinoid in combination with the specific PPAR agonists, WY
`14643, troglitazone and cabaprostacyclin affect differentiation
`and growth in cultured primary sebocyte-like rat preputial cells.26
`The enzymatic machinery for the local synthesis and
`metabolism of 1, 25-dihydroxyvitamin D (3) [1,25(OH)(2)
`D(3), calcitriol] has been also investigated in human sebocytes.
`Vitamin D receptor, vitamin D-25-hydroxylase, 25-hydroxyvi-
`tamin D-1alpha-hydroxylase and 1, 25-dihydroxyvitamin
`
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`Genetic/ extrinsic factors
`
`sex steroids/
`
`growth factors ~
`
`LXR ligands - - (cid:173)
`
`•
`histamines ~
`
`~ PPAR ligands
`0.--- neuropeptides
`
`cytokines ------.(cid:173)
`
`•
`
`vitamin D
`
`~
`
`ell prol;fe,atlon
`
`• cell differentiation
`
`• lipogenesis
`
`• hormone metabolism
`
`• cytokine and chemokine release
`
`Figure 2. Regulation of the biological function of human sebaceous gland cells.
`Schematic overview. [LXR: liver X receptors, PPAR: peroxisome-proliferator activated
`receptors].
`
`D-24-hydroxylase are expressed in SZ95 sebocytes
`in vitro. Furthermore, incubation of SZ95 sebocytes
`with 1,25(OH)(2)D(3) leads to a dose-dependent
`modulation of cell proliferation, cell cycle regulation,
`lipid content and interleukin (IL)-6/IL-8 secretion in
`vitro.27 In hamster auricular sebocytes while epider-
`mal growth factor and atRA can decrease the intracel-
`lular accumulation of triglycerides and free fatty acids
`in the cells, 1α, 25-dihydroxyvitamin D3 decreases
`the triglyceride level but augments the accumulation
`of wax esters. No difference has been detected in the
`level of cholesterol after the above treatments.28
`
`Effects of Hormones
`on Sebaceous Gland Cells
`
`Sex steroids. Several studies have demonstrated that
`there is an association between local overproduction
`of active androgens and acne. Acne patients produced
`higher rates of testosterone and 5α-dihydrotestosterone
`(5α-DHT) in their skin than healthy individuals.29
`High testosterone levels have been implicated with
`enhanced sebaceous gland activity in humans30,31 and
`consequently with diseases marked by hyperseborrhea,
`such as Acne vulgaris. However, only a few patients
`with androgenic disorders exhibit hyperandrogenemia, an observa-
`tion which indicates the predominance of peripheral tissue events
`for the occurrence of clinical signs.32
`Enhanced sebaceous gland activity is attributed to the potent
`androgen 5α-DHT5 as sebaceous gland cells possess all necessary
`enzymes for conversion of testosterone to 5α-DHT.33 The isozyme
`5α-reductase type I, which catalyses the conversion from testos-
`terone to 5α-DHT in peripheral tissues by a NADPH-dependent
`reaction is expressed predominantly in skin. It is present in the
`cytoplasm and cell membrane compartment in skin cells34 and
`particularly in facial sebocytes,33 illustrating the key role of seba-
`ceous gland cells in androgen metabolism.
`The effects of testosterone and 5α-DHT are mediated by bind-
`ing to the nuclear androgen receptor (AR), also expressed in human
`sebaceous gland cells.35 AR is a member of the steroid superfamily
`of ligand-dependent transcription factors. 5α-DHT binds to the
`AR with greater affinity than testosterone and the 5α-DHT/AR
`complex appears to be more stable36 and therefore, more effective.
`In contrast to the in vivo observations, in vitro experiments
`with human sebocytes have shown that testosterone affects pro-
`liferation in a dose-dependent manner6,37 but does not affect lipid
`synthesis.38,39 This contradiction has led to the assumption that
`co-factors may be required for the induction of the entire so-called
`androgenic influence of the sebaceous gland.40 Current research
`has indicated that PPAR and their ligands, may be the primary
`candidates.38,39 PPAR regulate multiple lipid metabolism genes
`in mitochondria, peroxisomes and microsomes, all prominent in
`sebocyte cytoplasm.38,39
`Indeed, Rosenfield et al.38 have previously demonstrated the
`interaction of 5α-DHT with PPAR ligands in inducing differ-
`entiation of sebocyte-like rat preputial cells and lipid synthesis.
`
`PPARα is the most important PPAR that regulates lipid synthesis
`and inflammation.40,41 In addition, PPAR-α, -δ, -γ1 and -γ2 have
`been shown to be expressed at mRNA and protein levels in SZ95
`sebocytes.39
`Dehydroepiandrosterone (DHEA) has been also shown to reg-
`ulate sebum production especially in postmenopausal women.22
`Consequently, several researchers have suggested the use of
`DHEA as an anti-aging agent.42,43 However, in in vitro experi-
`ments DHEA has been shown to have no direct effect on the bio-
`logical activity of human sebocytes. Substitution with DHEA in
`elderly persons is accompanied by a small increase of testosterone
`and estradiol, which may indeed yield an explanation of the clini-
`cal change demonstrated22 suggesting that the action of DHEA
`may be implemented through indirect pathways.
`Growth factors. Growth hormone (GH) activity is consid-
`ered to be mainly attributed to IGF but GH has also been shown
`to exhibit direct effects on human skin cells.44 The increased
`serum GH levels in acromegaly are associated with enhanced
`sebum secretion,45 an observation that could be confirmed by
`GH treatment of human SZ95 sebocytes in vitro.46 In acne vul-
`garis, increased sebum production peaks in mid-adolescence at
`a time that GH and IGF-I reach their highest serum levels.47 In
`mini rats, suppression of GH gene expression by an antisense
`transgene, leads among to thinner skin with less collagen and
`increase of subcutaneous adipose tissue also to small-sized seba-
`ceous glands.48
`Increased serum levels of IGF-I have been observed in adult
`women and men with acne and the number of total acne lesions,
`inflammatory lesions, serum levels of 5α-DHT and DHEA sul-
`phate, each correlated with serum IGF-I levels in women with
`acne.49,50 A correlation between the mean facial sebum excretion
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`rate and serum IGF-I levels has been demonstrated in postado-
`lescent acne patients.51 IGF-I has been localised to the peripheral
`cells of sebaceous glands in the rat,52 while in human skin the
`strongest expression of IGF-I protein has been found in maturing
`sebocytes and suprabasal cells of sebaceous ducts.53 The expres-
`sion of IGF-I receptor mRNA is the strongest in basal cells of
`sebaceous glands and immature sebocytes, whereas IGF-I recep-
`tor protein expression was uniform and intense in all regions of
`the gland.53 In animal studies, IGF-I has been shown to stimulate
`sebocyte differentiation in vitro especially in combination with
`GH,47 while in human keratinocytes it acts as a mitogen.54 On the
`other hand, in humans, IGF-I plays a key role in the induction of
`lipid synthesis in human sebocytes.46,55 In SEB-1 sebocytes, IGF-I
`increases lipogenesis by the induction of sterol response element-
`binding protein-1 (SREBP-1)55 through activation of PI3K/Akt
`and MAPK/ERK-signal transduction pathway.56 SREBP-1 pref-
`erentially regulates genes of fatty acid synthesis.56 In the hamster
`ear sebaceous model, androgens rapidly induce the expression of
`SREBP-1.57 In addition, an interaction between the IGF-I and
`estradiol signalling pathway has been described in human SZ95
`sebocytes, implicating that estrogens may have an indirect effect
`on the pathogenesis of acne.46
`Recent data suggest that incubation of human sebaceous
`gland cells with a hormone mixture consisting of growth fac-
`tors and sex steroids at age-specific levels may alter the biological
`activity of the cells by regulating their transcriptome and thus
`illustrate the importance of the hormone environment for cell
`function.58 Human SZ95 sebocytes treated with hormone lev-
`els that can be found in 60 year-old women produce less lipids
`than sebocytes treated with a hormone mixture representing
`that found in serum of 20 year-old women.58 Gene expression
`profiling via cDNA microarray between SZ95 sebocytes under
`the 20 and 60 year-old hormone mixture detected differentially
`expressed genes, which are involved in biological processes such
`as DNA repair and stability, mitochondrial function, oxidative
`stress, cell cycle and apoptosis, ubiquitin-induced proteolysis and
`transcriptional regulation. The most significantly altered signal-
`ling pathway was that of transforming growth factor-β (TGFβ).
`A disturbed function of this cascade has been also associated with
`tumourigenesis, i.e., in pancreatic, prostate, intestine, breast and
`uterine cancer. Interestingly, genes expressed in signalling path-
`ways operative in age-associated diseases such as Huntington’s
`disease, dentatorubral-pallidoluysian atrophy and amyotrophic
`lateral sclerosis were also identified. These data demonstrate that
`hormones interact in a complex fashion, and sebocytes may be
`affected to a large extent by the changes in their circulating blood
`levels with age.58
`
`Effects of NPs on Sebaceous Gland Cells
`
`NP are a heterogeneous group of biologically active peptides that
`are present in neurons of both the central and peripheral ner-
`vous systems. However, human skin and in particular the human
`sebaceous gland has been shown to express functional recep-
`tors for NP, such as corticotropin-releasing hormone (CRH),
`melanocortins, β-endorphin, vasoactive intestinal polypeptide,
`
`neuropeptide Y and calcitonin gene-related peptide. These recep-
`tors modulate the production of inflammatory cytokines, prolif-
`eration, differentiation, lipogenesis and androgen metabolism in
`human sebocytes.5
`CRH the most proximal element of the hypophysis-pituitary-
`adrenal (HPA) axis acts as central coordinator for neuroendo-
`crine and behavioural responses to stress. It has been shown that
`CRH, CRH-binding protein, CRH-receptor®1 and CRH-R2
`are expressed in SZ95 sebocytes at mRNA and protein level,
`while CRH-R1 is the predominant type (CRH-R1/CRH-R2 =
`2). In addition, CRH significantly induces sebaceous lipids pro-
`duction, IL-6 and -8 synthesis and may upregulate mRNA levels
`of 3β-hydroxysteroid dehydrogenase/Δ5-4 isomerase.59,60 In acne-
`involved skin the complete CRH system is abundant especially in
`the sebaceous glands (Fig. 3), possibly activating pathways which
`affect immune and inflammatory processes leading to the devel-
`opment and stress-induced exacerbation of acne.61
`Melanocortin (MC) peptides can also directly affect the
`function of human sebocytes via MC receptors. α-Melanocyte-
`stimulating hormone (α-MSH) has been demonstrated to act as
`a modulator of the rat preputial gland, a specialised sebaceous
`gland-like structure of rodents.62 The presence of both MC-1R
`and MC-5R which bind α-MSH were detected in primary cell
`cultures of facial human sebocytes. The expression of MC-5R is
`weaker than that of MC1-R but it has been shown to be a marker
`of human sebocyte differentiation, since it is expressed in dif-
`ferentiated, lipid-containing sebocytes only.63,64 In acne-involved
`skin, sebocytes and keratinocytes of the ductus seboglandularis
`showed very intense MC-1R expression in contrast to less intense
`scattered immunoreactivity in normal skin samples suggesting
`that this receptor is involved in the initiation of acne.65 MC-1R
`expression has been shown to be upregulated by proinflamma-
`tory signals.66,67 As proinflammatory cytokines are upregulated
`in acne lesions,68 sebocytes may respond to these signals with
`increased MC-1R expression, thereby generating a negative feed-
`back mechanism for α-MSH which exerts direct anti-inflamma-
`tory actions, i.e., inhibition of IL-1-mediated IL-8 secretion.64,65
`Cannabinoid receptors (CR), which mediate the psychophar-
`macological action of marijuana have been not only localised in
`the central and peripheral nervous system but also in human skin.
`CR1 and 2 are expressed in human sebaceous glands,69 whereas the
`CB2 and other prototypic endocannabinoids are present in SZ95
`sebocytes and may induce in a dose-dependent manner lipid pro-
`duction and cell death. These actions are selectively mediated by
`CB2-coupled signalling involving the MAPK pathway.70
`Other NP such as substance P or vasointestinal peptide may
`also be involved in the pathogenesis of acne vulgaris Substance
`P, which can be elicited by stress may promote the development
`of cytoplasmic organelles in sebaceous cells, stimulate sebaceous
`germinative cells, and induce significant increases in the area of
`sebaceous glands. It also increases the size of individual sebaceous
`cells and the number of sebum vacuoles for each differentiated
`sebaceous cell, all of which suggests that substance P promotes
`both the proliferation and the differentiation of sebaceous
`glands. Substance P induces the expression of neutral endopep-
`tidase, a potent NP-degrading enzyme, in sebaceous germinative
`
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`Figure 3. Localisation of CRH immunostaining in the sebaceous gland of acne patients (A) and in the normal skin of healthy controls (B). Very intensive
`expression of the gene in all types of sebocytes—basal, differentiating and mature cells—and keratinocytes of ductus seboglandularis in acne skin
`is shown (A) (x400); significant weaker and dependent upon sebocytes differentiation stage immunoreaction of sebaceous gland in normal skin (B)
`(x400).
`
`cells and of E-selectin by perisebaceous venules. Facial skin from
`acne patients is characterised by rich innervation, by increased
`numbers of substance P-containing nerves and mast cells, and by
`strong expression of neutral endopeptidase in sebaceous glands
`and E-selectin in venules around sebaceous glands, compared
`with normal skin.71 The ectopeptidases dipeptidyl peptidase
`IV (DP IV or CD26) and aminopeptidase N (APN or CD13),
`which have been shown to be involved in the degradation of sev-
`eral NP, especially of substance P, have been found to be highly
`expressed in human sebocytes in vivo and in vitro. Further stud-
`ies have shown unexpectedly that inhibitors of DP IV and APN
`can suppress proliferation and slightly decrease neutral lipids,
`but can also enhance terminal differentiation in SZ95 sebocytes.
`This suggests that ectopeptidases may be new targets to modulate
`certain sebocyte functions, and that ectopeptidase inhibitors may
`have potential therapeutic roles in acne pathogenesis.72
`A central integrator of nociception, the transient recep-
`tor potential vanilloid-1 (TRPV1) is expressed in human skin,
`sebaceous glands in situ and in SZ95 sebocytes in vitro. It has
`
`been documented that the prototypic TRPV1 agonist, capsaicin,
`selectively inhibits basal and arachidonic acid-induced lipid syn-
`thesis in a dose-, time- and extracellular calcium-dependent and
`TRPV1-specific manner. Low-dose capsaicin stimulates cellular
`proliferation via TRPV1, whereas higher concentrations inhibit
`sebocyte growth and induce cell death independent of TRPV1.73
`These findings suggest the strong involvement of neurogenic fac-
`tors and sebocytes in the disease process of acne.
`
`(cid:44)(cid:81)(cid:193)(cid:68)(cid:80)(cid:80)(cid:68)(cid:87)(cid:76)(cid:82)(cid:81)(cid:15) (cid:54)(cid:72)(cid:69)(cid:68)(cid:70)(cid:72)(cid:82)(cid:88)(cid:86) (cid:42)(cid:79)(cid:68)(cid:81)(cid:71) (cid:38)(cid:72)(cid:79)(cid:79)(cid:86) (cid:68)(cid:81)(cid:71) (cid:36)(cid:70)(cid:81)(cid:72)
`
`Inflammation is being regarded as a key component of the patho-
`genesis of acne.74 In the last few years, there has been a debate as
`to whether hyperkeratinisation of the follicular duct precedes the
`influx of inflammatory cells or vice versa. Recent studies support
`the latter hypothesis by demonstrating that an increase in IL-1
`activity occurs before the hyperproliferation around uninvolved
`follicles and this triggers the activation of the keratinocytes.68,75
`Expression profiling of acne-involved and uninvolved skin from
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`proliferation and may play a profound role in the transformation
`of a normal follicle into an acne lesion.68
`Inflammation is further characterised by action of active lipid
`mediators, such as leucotrienes (LT), prostaglandins (PG) and
`15-hydroxyeicosatetraenoic acids (15-HETE). These molecules are
`synthesised from arachidonic acid (AA) or linolenic acid by the
`enzymes lipoxygenase (LOX) and cyclooxygenase (COX), respec-
`tively. Both COX isozymes, COX-1 and COX-2, are expressed
`in human sebocytes in vitro, in particular COX-2 expression is
`selectively upregulated in acne involved sebaceous glands in vivo41
`(Fig. 4). In hamster sebocytes the expression of COX-2 has been
`also documented,78 while the 15-desoxy-Δ12,14-PGJ2 has been
`shown to induce the lipid synthesis in the cells.79 Activation of the
`platelet-activating factor signalling pathway (PAF, 1-O-alkyl-2-
`acetyl-sn-glycero-3-phosphocholine) which consists of a group of
`phosphocholines with various biological effects, including modula-
`tion of keratinocyte function and skin inflammation, can regulate
`the expression of inflammatory mediators, e.g., COX-2 and PGE2,
`as well as IL-8 in SZ95 sebocytes.80 Transgenic keratin 5 promoter
`driven overexpression of COX-2 in the basal compartment of the
`epidermis of the mouse and increased PGE2 levels have been doc-
`umented to cause sebaceous gland hyperplasia and overshooting
`sebum production pointing to a role of COX-2-mediated PGE2
`synthesis in this process.81 Activation of PPARγ by UVB irradia-
`tion and the potent lipid soluble oxidant tert-butylhydroperoxide
`(TBH) induces COX-2 expression in SZ95 sebocytes and this find-
`ing indicates a PPARγ COX-2-mediated pathway regulating sebo-
`cyte proliferation and/or lipogenesis.82
`LT are potent proinflammatory mediators and neutrophil
`attractants produced from arachidonic acid by the enzyme 5-LOX.
`Human sebocytes express all necessary enzymes for a functional LT
`pathway. The enzymes 5-LOX and LTA4 hydrolase are expressed
`in SZ95 sebocytes at protein and mRNA level. These enzymes are
`essential for the formation of LTB4. On the other hand, 15-LOX
`expression shows a weak expression in SZ95 sebocytes, indicating
`that sebocytes do not play a significant role in the biosynthesis of
`the anti-inflammatory 15-HETE. Treatment of SZ95 sebocytes
`with AA stimulates 5-LOX expression and induces LTB4 synthe-
`sis.41 In addition, AA induces the expression of the IL-6 and IL-8
`cytokines. 5-LOX and LTA4 hydrolase show a stronger expression
`in acne lesions than in normal skin and in uninvolved skin of acne
`patients.41 The involvement of 5-LOX in the pathogenesis of acne
`has led to new therapeutic strategies to deal with the disease.83
`Cytokines are present in normal sebaceous glands, and they are
`affected by many factors. IL-1α, TNFα, IL-6 and IL-8 are released
`into supernatant in unstressed sebocyte culture.41 In a stressed
`environment, the amounts of released cytokines increase signifi-
`cantly. AA and calcium ionophore enhance the level of IL-6 and
`IL-8, but that of IL-1β and TNFα is not affected.9,41
`Psoriasin, a member of the S100 gene family, was shown to be
`highly expressed in the epidermis and the ductus seboglandularis
`of acne-involved skin in contrast to uninvolved control.84 Psoriasin
`has been suggested to be involved in the pathogenesis of several
`inflammatory skin diseases, and its levels increase in response to
`inflammatory stress. RA and inflammatory agents have been also
`implicated in the upregulation of psoriasin.85,86
`
`Figure 4. Localisation of COX-2 immunostaining in the sebaceous gland
`of acne patients (A) and in the normal skin of healthy controls (B). Very
`strong immunoreaction of the gene within the sebaceous gland of acne
`skin, especially, in undifferentiated and early differentiated sebocytes
`is seen (A) (x400). Weak immunoexpression of COX-2 in the sebaceous
`gland and ductal cells of healthy skin (B) (x400).
`
`acne patients and from subjects without acne via cDNA micro-
`arrays have given us a better insight into the etiological factors
`giving rise to acne.76 In inflammatory acne lesions, the major-
`ity of the regulated genes, which showed to be upregulated are
`involved in inflammatory processes. These include matrix metal-
`loproteinases, β-defensin 4, IL-8 and granulysin. No differ-
`ences were noted between normal skin from acne patients and
`that from patients without acne in the array analysis. NFκB, a
`transcription factor critical for upregulation of many proin-
`flammatory cytokine genes has been shown to be activated in
`acne lesions.77 NFκB-regulated cytokine mRNA genes levels
`of TNFα, IL-1β, IL-8 and IL-10 are significantly upregulated
`in acne-involved skin compared to uninvolved normal adjacent
`skin. Elevated expression of the chemokine IL-8 is able to attract
`circulating inflammatory cells into the tissue. Indeed, in lesional
`skin of acne, there is a marked increase in the presence of neutro-
`phils, as compared to the uninvolved skin whereas lymphocytes
`are prominently visible in inflammatory acne lesions as compared
`to normal controls.77 Another transcription factor involved in
`inflammation, AP-1 has been shown to be activated in inflamma-
`tory acne lesions in vivo as well. Levels of the proinflammatory
`cytokine IL-1 were also upregulated perifollicularly in unin-
`volved skin from acne patients. This cytokine may be responsible
`for the cutaneous inflammation and the resulting keratinocyte
`
`46
`
`Dermato-Endocrinology
`
`Volume 3 Issue 1
`
`6 of 9
`
`

`

`Propionibacterium acnes (p. acnes)
`
`P. acnes is a gram-positive anaerobic bacterium which with other
`non-pathogenic microorganisms, such as coagulase negative staph-
`ylococci and diphtheroid rods, resides in pilosebaceous follicles as a
`member of the resident bacterial flora. The mechanism by which P.
`acnes contributes to the pathogenesis of acne is debated. While in
`several studies it could be shown that P. acnes numbers are higher
`in acne patients than in healthy individuals, other studies found no
`difference between the numbers of P. acnes in affected and non-
`affected follicles. Nevertheless, an abnormal colonisation by P.
`acnes has been implicated in the occurrence of acne via the induc-
`tion of inflammatory mediators. The bacteria stimulate the pro-
`duction of proinflammatory cytokines, including interleukins-1β,
`-8 and -12, and TNFα. It is known that P. acnes-induced cytokine
`production is mediated by Toll-like receptor (TLR) 2.87-90 The
`pilosebaceous unit is an immunocompetent organ. Keratinocytes
`and sebocytes may act as immune cells capable of pathogen rec-
`ognition and abnormal lipid presentation. Both cell types can be
`activated by P. acnes via toll-like receptors (TLR), CD14 and CD1
`molecules.88 The expression of TLR2, TLR4, TLR6 and CD14
`has been already documented in SZ95 sebocytes.91,92 Recent evi-
`dence has indicated that human sebaceous glands may contribute
`to the skin immune defense by releasing antimicrobial peptides
`(AMP). For example, human β-defensins (hBD) are expressed in
`human pilosebaceous units and their expressio