Dermatol Clin 25 (2007) 577–588

Receptors of Eccrine, Apocrine, and HolocrineSkin Glands

Uwe Wollina, MDa,*, Mohamed Badawy Abdel-Naser, MDb,Ruta Ganceviciene, MDc,d, Christos C. Zouboulis, MDc,e

aDepartment of Dermatology and Allergology, Academic Teaching Hospital Dresden-Friedrichstadt,

Friedrichstrasse 41, 01067 Dresden, GermanybFaculty of Medicine, Ain Shams University Hospital, 4 Al Rahman Tower 11281, El Sawah Square, Cairo, Egypt

cLaboratory for Biogerontology, Dermato-Pharmacology and Dermato-Endocrinology,

Institute of Clinical Pharmacology and Toxicology, Charite Universitaetsmedizin Berlin,

Campus Benjamin Franklin, 12200 Berlin, GermanydDepartment of Dermatology, Vilnius University Hospital, Santariskiu Klinikos, Vilnius, Lithuania

eDepartment of Dermatology, Venereology, and Allergology, Dessau Medical Center, 06847 Dessau, Germany

Eccrine, apocrine, and holocrine glands belongto the group of specialized miniorgans of skinknown as skin appendages. Eccrine glands de-

velop from the sweat gland anlagen in thepalmoplantar skin between 14 to 16 weeks’estimated gestational age (EGA). Canalization

of the dermal component (ie, coils and dermalduct) is complete by 16 weeks’ EGA. Canalizationof the epidermal duct or acrosyringium is notcomplete until 22 weeks’ EGA. The specific end

product of eccrine glands is sweat. They do notfunction in utero but start functioning immedi-ately after birth.

Apocrine glands usually arise from the upperportion of hair follicles not before the fifth monthof EGA. They function transiently during the

third trimester and become quiescent in theneonate. Their function reappears during puberty.Their secretions play a role in sexuality. Apocrine

glands, such as Moll’s glands of the eyelid,contribute to ocular host defense. The largestapocrine gland, however, is the breast gland,which is not discussed in this article.

The development of holocrine sebaceous glandsis associated closely with the formation of hairfollicles during embryonic life. They rest until

puberty. Their specific end product is sebum [1,2].

* Corresponding author.

E-mail address: wollina-uw@khdf.de (U. Wollina).

0733-8635/07/$ - see front matter � 2007 Elsevier Inc. All

doi:10.1016/j.det.2007.06.001

Sex steroid receptors

Sex-steroid receptors are distributed widelyamong human tissues. As an example of their ac-

tion, the estrogen receptors (ERs) are discussed inmore detail.

Estrogens effects are genomic or nongenomic.

Estrogens mediate their genomic activity by in-teraction with and activation of specific nuclearERs. The ER-ligand complex binds to specificDNA sequences within the regulatory region of

the target genes. By interaction with other cellularcomponents, these target genes are activated orsuppressed. This is known as the classical path-

way. The nonclassical pathway of genomic actionalso can be mediated by interactions with ERs, inthis case with membrane-bound ERs localized in

the caveolae. Another option is the binding toG-protein–coupled receptor. This interaction ac-tivates kinases that act on nuclear transcription

factors (ie, nongenomic) [3,4].Two isoforms of ERs are known (ie, ER-a and

ER-b). Whereas a large number of natural andsynthetic estrogens show a similar binding affinity

to both receptors, other ligands are more selective,such as genistein or daidzein, which activateER-b much more strongly. ER immunostaining

usually is seen in a nuclear pattern [5].ER-a is expressed exclusively in basal and

partially differentiated cells of normal sebaceous

glands but not in sebaceous tumors. ER-a is seen in

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578 WOLLINA et al

only a small portion of the eccrine gland epitheliawith a weak cytoplasmic staining. ER-b is ex-pressed by sebaceous glands and cultured human

sebocytes in the same distribution as ER-a [6]. Hu-man eccrine sweat glands express ER-b. In mousesebaceous glands there is a gender difference inthe expression of ERs and androgen receptors

(ARs) [7] but in human skin there is no gender dif-ference in the pattern or distribution of ERs [8].Treatment of gonadectomizedmalemicewith pros-

taglandin E2 leads to expression of ER-a [7].ER-b expression is diminished in many human

eccrine neoplasms [9,10]. A case of a 45-year-old

woman who had a signet cell carcinoma of the ec-crine sweat gland of the eyelid, however, showedpositivity for ER and progesterone receptor(PR) [11]. Cases of ER-positive malignant eccrine

spiradenoma also are described [12]. In the axil-lary apocrine glands, a strong nuclear expressionof ER-a is seen in the secretory epithelium [13].

Sebaceous glands belong to the peripheralintracrine tissues in which estrogens are formedby transformation of prohoromone, dehydroe-

piandrosterone (DHEA), locally. There is noDHEA receptor in human tissue but DHEA isa major source of estrogen in women. Oral DHEA

supplementation in postmenopausal women whohave mostly sebostatic skin is capable of increas-ing sebum production by almost 80% after 12months. Apart from this, other beneficial cutane-

ous effects are documented, such as improved skinhydration, reduced facial pigmentation, and in-creased skin thickness [14,15].

PRs a and b have been identified in humanskin. In normal sebaceous glands, PRa and PRbare expressed by basal and differentiated sebo-

cytes [9]. PR expression has been observed in sy-ringoma, suggesting the possibility of hormonalcontrol of this benign eccrine tumor [16,17].

ARs are expressed strongly by all sebocytes, in

eccrine and apocrine sweat glands [18]. In seba-ceous glands, undifferentiated basal sebocytes ex-press AR in higher quantity than differentiated

sebocytes [19]. In eccrine and apocrine sweatglands, luminal cells of the secretory portion arevariably AR reactive [20]. In male mice, but not

in female animals, gonadectomy leads to a diminu-tion of the AR expression by sebaceous glands [7].

In benign eccrine tumors, the expression of AR

is diminished [9]. In apocrine carcinoma, AR andAR messenger RNA (mRNA) may be absent [21].ARs are expressed by sebaceous and sweat glandswithin nevus sebaceous of Jadassohn [22]. Papil-

lary hidradenomas may overexpress AR [23].

In addition, AR is expressed by the secretoryepithelium of axillary apocrine glands in correla-tion to their secretory activity [13]. An exception

to this rule is the apocrine gland of the eyelid (ie,Moll’s gland). Not all primates express ARs inthis gland [24]. In patients who have nonautoim-mune dry eyes with meibomian gland dysfunc-

tion, the level of bioavailable testosterone isreduced significantly [25].

The available data suggest that all adnexal

glands of human skin interact with sex steroids.This can be of developmental importance, such asfor sebaceous glands during puberty, or of regu-

latory importance, such as in apocrine glands,where phermones are produced under the influ-ence of androgens [2,13].

Extramammary Paget’s disease is an uncom-

mon neoplasm of the skin with apocrine differen-tiation. Eighty percent of these tumors and manyof the lymph node metastases are AR positive

[26]. These tumor cells are characterized, however,by a consistent lack of ERs and PRs [27].

In the case of acne, the adenarche (ie, the

starting point of endogenous androgen produc-tion) sebaceous glands increase their volume andtheir sebum production [2,28]. A major stimulus

for this is the DHEA, later on testosterone playsa major role. There is no acne without androgens.In women who have acne, the androgen effectscan be balanced with lower doses of estrogen com-

bined with progestins, such as levonogestrel, deso-gestrel, norgestinate, gestodene, cyproteroneacetate, chlormadinone acetate, and drospirenone

[29]. Studies of oral contraceptives show them tobe efficient and safe in women, reducing inflam-matory and noninflammatory lesions [29,30].

In therapeutically resistant cystic acne of menand women, an androgen excess occurs. DHEAsulfate and 17-0H-progesterone levels are higherand sex-hormone–binding globulin is lower in

affected subjects compared with controls.Therefore, low-dose dexamethasone can be usedfor 6 months to decrease DHEA sulfate [31]. In

hyperandrogenism, with the triade of acne, alope-cia, and hypertrichosis, contraceptives and antian-drogens are the cornerstone of treatment [32].

In ER-positive sweat gland adenocarcinoma,the use of hormone-blocking agents, such astamoxifen, has been discussed for the treatment

of metastasizing disease [12,33,34].Luteinizing hormone/human chorionic gonad-

otrophin receptor (LH/hCG-R) was detected inskin by immunohistochemistry and reverse tran-

scription polymerase chain reaction. In eccrine

579RECEPTORS OF SKIN GLANDS

sweat glands, LH/hCG-R is localized in clearcells that are involved in fluid and ion transport.Changes in sweating during puberty andmenopause might be related to changes in LH

levels. In the secretory coils, cells adjacent to thebasement membrane were stained with mono-clonal antibody against LH/hCG-R. In seba-

ceous glands, thin cells with round nuclei closeto the duct were stained intensively, whereaspolyhedral sebocytes with fat droplets showed

a faint staining [35].

Mineralocorticoid and glucocorticoid receptors

Mineralocorticoid receptor (MCR) mediates

aldosterone actions on salt and water balance inrestricted target cells. MCR is a member of thenuclear receptor superfamily and acts as a ligand-induced transcription factor modulating the

expression of specific proteins involved in physi-ologic responses to aldosterone [36]. Two humanMCR isoforms are identified (ie, a and b). Bothisoforms are coexpressed in sweat gland ducts.In patients who have abnormal mineralocorticoidstatus, the expression may be compromised. In

primary hyperaldosteronism and Liddle syn-drome, MCRb but not MCRa expression in sweatglands is reduced markedly [37].

The enzyme, 11-b-hydroxysteroid dehydroge-nase type II, is shown to confer specificity onMCR by inactivating glucocorticoids. Colocaliza-tion of the enzyme and the MCR is seen in

a majority of sodium-transporting epithelia. Inskin, MCR is expressed in basal cell of the sweatducts but not in apocrine or sebaceous glands.

The dehydrogenase is localized in luminal epithe-lia of the eccrine duct [38].

Like ARs or PRs, unliganded glucocorticoid

receptors (GCRs) are located in the cytoplasmattached to heat shock proteins (hsp 90, 70, and56). When hormones bind to GCRs, hsps are

released and, through an energy-dependent process,the hormone receptor complexes form homo- orheterodimers. The zinc fingers of their DNAdomains slot into the glucocorticoid response

elements in the DNA helix where they exertactivation of suppression of protein synthesis. Inaddition, nongenomic effects of glucocorticoids

are mediated by interaction with surface proteinsand lipids [39].

GCRs immunoreactivity is found in sweat

gland and sebaceous gland epithelia [40]. Thisprobably explains the induction of steroid-induced acne.

Orphan nuclear hormone receptors

Nuclear hormone receptors are important inthe regulation of epithelial cell differentiation andlipid metabolism. Different receptors are identified

in human skin. Some of them play a crucial role inlipid metabolism of sebaceous glands. In seba-ceous glands maintained ex vivo and in human

sebocyte cultures, peroxisome proliferation-activated receptors (PPARs) (types a, d, and g),retinoid X receptor (RXR)-a, liver X receptor-a,and pregnane X receptor but not farnesoid Xreceptor could be detected (Fig. 1) [41–43]. AllPPARs subtypes also are expressed in sebaceous

glands in vivo. Furthermore, DAX1 and SF1 areexpressed by sebaceous glands and cultured hu-man sebocytes and eccrine sweat glands in humanskin [44,45].

PPARa and PPARg ligands inhibited the lipidsynthesis in sebaceous glands maintained ex vivo[42] but stimulated lipogenesis in diabetic patients

in vivo [46]. In agreement with the in vivodata, natural and some synthetic PPARa, g, anda/d agonists increased lipid synthesis in human

sebocytes cultures (SZ95 and SEB-1 cell lines)[43,46,47].

Investigations on human SZ95 sebocytes in

vitro suggest that PPARg activation by ultravioletlight B irradiation and PPARg-dependent cyclo-oxygenase-2 activation are important regulatorsof cellular responses to oxidative stress [48]. Inhi-

bition of the synthesis of the natural PPARa ago-nist leukotriene B4 in vivo led to significantimprovement of inflammatory acne lesions and

seborrhoea [49–51].In sebocyte development, there is a limited

cooperation between PPAR and RXR agonists.

In vitro, a submaximal dose of rexinoidda RXRagonistdaugmented the stimulation of sebocytedifferentiation by PPAR agonists [52].

The development of new RXR agonists might

lead to cancer prevention for diseases, such asMuir-Torre syndrome, where sebaceous tumorsarise on skin [53].

Neurotrophic factor receptor

Ret is the specific receptor for glial cell line–derived neurotrophic factor (GDNF), a factor

initially identified as a neurotrophic factor fordoaminergic neurons. Ret was found in rats in theepithelial cells of the secretory duct and the coiled

secretory terminal of eccrine sweat glands. Electronmicroscopy showed thatRet immunoreactivity waslocalized in the basal area of secretory cells adjacent

580 WOLLINA et al

Fig. 1. Expression of PPARa, PPARd, and PPARg1 in normal human sebaceous glands. Strong expression of PPARg1

and weaker of PPARa and PPARd are seen. Skin biopsies were fixed in spirit-formol (9:1) fixative for 12 hours at 4�C,rinsed in 0.01-M phosphate-buffered saline (PBS) (pH 7.6), embedded in paraffin, and sectioned (2 to 3 Um thick). Sec-

tions were then heated to 60�C to melt paraffin and deparaffinized in xylene, followed by a rehydration for 1 minute

through a graded series of ethanol. The sections were then incubated with PPARg monoclonal antibody for 1 hour

and PPARd or PPARg1 overnight (from Santa Cruz, Heidelberg, Germany) at room temperature. Before incubation

with the PPARd primary antibody, high-pressure boiling of the specimens for 3 minutes in a pressure cooker with citrate

buffer was performed. Primary monoclonal antibodies were added at dilutions 1:100 (PPARa) or 1:50 (PPARd,

PPARg1). The negative control consisted of sections incubated with antibody diluent instead of the primary antiserum.

Subsequently, the sections were incubated with a biotinylated secondary antibody (diluted 1:500) for 30 minutes and

then with a streptavidine enzyme conjugate. Finally, the sections reacted with a fuchsin substrate chromogen system

for 5–10 minutes and were couterstained with Mayer’s hematoxylin. (From Alestas T, Ganceviciene R, Fimmel S,

et al. Enzymes involved in the biosynthesis of leukotriene B4 and prostaglandin E2 are active in sebaceous glands.

J Mol Med 2006;84:80; with kind permission from Springer Science and Business Media.)

to myoepithelial cells. The ligand GDNF wasobserved in most myoepithelial cells of the secre-tory coils and in a fewnervefibers innervating sweat

glands. It is suggested that GDNF plays a trophicrole for sweat glands [54].

Another receptor of the GDNF family is glial

cell line-derived neurotrophic factor-family recep-tor (GFR) a2, a receptor that is important for thedevelopment of parasympathetic and enteric neu-rons. In a GFR a2-knockout mouse model, the

density of sympathetic sweat gland innervationwas reduced by 50% to 70% [55].

Vanilloid and cannabinoid receptors

The family of vanilloid receptors (VRs) in-

cludes VR1, vanilloid-like proteins 1 and 2, andVR 50-splice variant. In skin, the VR1 is distrib-uted widely in human tissues. It is a nonselective

cation channel that binds capsaicin. VR1 is acti-vated by endogenous factors, such as increase ofthe body temperature or decrease of pH or anand-

amine compounds. VR1 immunoreactivity is seenin differentiated sebocytes and the secretory por-tion of eccrine sweat glands. They seem to be

involved in neurogenic inflammation, tempera-ture, and pH control [56].

Cannabinoid receptors mediate the psycho-

pharmacologic action of marijuana and are local-ized in the central and the peripheral nervoussystems, as well as on cells of the immune system.

CB1 and CB2 also are expressed by sebocytes andeccrine sweat glands [57].

Endovanilloids, cannabinoids, and opioidsfunction as intracutaneous itch mediators and

likely are involved in skin-derived, pruritogenicpruritus [58,59]. The use of specifically designedligands to such receptors will open a new avenue

for the treatment of itch.

Nicotinic and muscarinic acetylcholine receptors

Acetylcholine (Ach) has two types of receptors,

nicotinic and muscarinic. The nicotinic ACh re-ceptor (nAChR) is a 290-kd protein that consistsof a ring of five similar subunits. Seventeen

nAChR subunits are identified: a1–10, b1–4, g,d and 3. They form ion channels with differentfunctional and pharmacologic characteristics.

581RECEPTORS OF SKIN GLANDS

Nicotin is an ACh antagonist and interacts withall AChR types except a9 subunits [51].

Five subtypes of muscarinic AChR (mAChR)are known. The mAChRs are expressed by

keratinocytes in human epidermis and skinglands. The mAChRs are involved in the earlysteps of embryologic differentiation of eccrine

sweat glands. During development, the innerva-tion of eccrine sweat glands undergoes a strikingchange from noradrenergic to cholinergic func-

tion. In rat skin it was observed that mAChRs aredetectable as early as postnatal day 4 when glandsbegin to form. Within the next 2 weeks, m3 AChR

protein and mRNA increase. m3 AChR expres-sion does not depend on intact gland innervation.The m3 AChR is coupled to phospholipase C [60].

Muscarinic blockage during development or in

adult animals results in the loss of secretoryresponsiveness, which is regulated by innervation[61]. In postnatal life, ACh is the major transmit-

ter for sudomotoric activity and seems to be ofimportance for sebaceous gland activity. In ratskin, m2 AChR is expressed by nerve fibers that

innervate eccrine sweat glands [62] but m3AChR seems to be the major receptor subtype inthe regulation of sweat gland secretion [63].

Scopolamin is a substance with similar bindingaffinities to all of the five known muscarinicreceptor subtypes. By 0.6-mg scopolamine givenorally, a significant reduction of sweat gland

activity occurs as measured by skin conductancein normal adult volunteers [64].

In undifferentiated sebocytes, the nAChR sub-

units a3, a9, b4, and mAChR subtypes m2–m5are found. Mature sebocytes express a7, b2, b4,m2, and m4 AChR. In eccrine sweat glands, the

a3, a7, and m2–m5 AChR are most prominent inmyoepithelial cells whereas a9, b2, m1, m3, andm4 AChR are present in acinar epithelia [65].

The expression of a7 AChR is abolished in the

epidermis adjacent to the acrosyringium in pal-moplantar pustulosis, a disease associated withnicotine abuse [66]. Dysfunction of mAChR is

a possible cause of idiopathic sudomotor failure(a disease with sudden onset, concomitant sharppain, or cholinergic urticaria over the entire

body), elevated serum IgE, lack of autonomic dys-function other than generalized anhidrosis, andmarked response to steroids. Although thermo-

regulatory sweating is absent, emotional sweatingis preserved [67].

Botulinum toxin is the most potent pharma-cologic inhibitor of focal hyperhidrosis. It

blocks specific intracellular transport proteins

of ACh but itself does not interact with anyAChR [68].

Goldstein and colleagues [69] reported a patientwho had frequent episodes of pain, sweating, and

flushing bilaterally in the hairless skin of the oph-thalmic and maxillary distributions of the trigem-inal nerve. The patient reported benefit from

anticholinergic quarternary amine trospium chlo-ride whereas intravenous edrophonium evokedpain and sweating. The authors concluded that

facial pain and sweating can result from by occu-pation of muscarinic cholinergic receptors afterACh release from local nerves.

Angiotensin II receptors

The tissue response to angiotensin IIdanoctapeptide that regulates blood pressuredis

mediated by specific cell surface receptors, AT1and AT2. AT1 is predominant in the vascularsystem. AT1 is expressed by eccrine and apocrine

sweat glands. In apocrine glands, luminal andperiluminal cells of the acrosyringium are AT1positive. The luminal cells of the dermal ductexpress AT1 whereas the basal cells, secretory

cells, and myoepithelial cells are negative. Thewhole gland is AT2 negative. In eccrine sweatglands, the complete acrosyringium and the lumi-

nal cells of the dermal duct are AT1 positive andthe remaining cellular elements negative. AT2 isnot expressed by eccrine sweat glands [70]. AT1

also is found in sebaceous glands [71].In eccrine poroma, some of the tumor cells in

cell strands and cells surrounding luminal struc-

tures are AT1 positive; AT2 is not expressed [70].

Melanocortin receptors

Melanocortins regulate immune functions,

pigmentation, lipid metabolism, and adrenalhormone secretion. Melanocortins include adre-nocorticotrophic hormone, a-melanocyte-stimu-

lating hormone (aMSH), b-lipotrophin, andendorphins. Melanocortins bind to specificG-protein coupled receptors. Five different mela-nocortin receptor (MR) subtypes are known [72].

MR-1 transcripts and immunoreactivity areseen in sebocytes in vitro and in vivo. Sebumproduction can be increased by aMSH. By in-

teraction of aMSH with MR-1, interleukin (IL)-8expression of sebocytes is modulated. Immunoe-lectronmicroscopy demonstrates MR-1 along the

cell surface and intracytoplasmatically withintubular endosomes, suggesting the internalizationof MR-1 [73].

582 WOLLINA et al

MR-1 is expressed by a variety of sebaceousmalformations, hamartomas, and neoplasms,such as sebaceoma, cylindroma, and extramam-

mary Paget’s disease. MR-1 is found in eccrinesweat glands in dermal ducts and secretoryepithelia. Eccrine tumors, such as syringoma orhidroacanthoma simplex, also express this type of

MR [74].MR-5 is expressed by differentiating, lipid-

laden sebaceous cells but not in basal sebocytes.

Therefore, MR-5 seems to represent a sebocytedifferentiation marker [75]. In transgenic mice,a targeted disruption ofMR-5 resulted in amarked

decrease in sebum production by sebaceousglands. MR-5 also is expressed by eccrine sweatglands [76]. Others could not identify MR-5immunoreactivity in sebaceous glands [73].

Because melanocortins can suppress in-flammation by prevention of nuclear factor kBactivation, MR ligands are of potential creating

new anti-inflammatory acne drugs [77].

Further neuropeptide receptors

Vasoactive intestinal peptide receptor (VIP-R)has been localized by immunohistochemistry in

acinar cells of the secretory coil and in luminalcells of the duct in eccrine sweat glands. It hasbeen suggested that VIP is involved in regulation

of chloride reabsorption from primary sweat atthe ductal segment [78]. Further analysis revealedthat two functional receptor types are expressed,namely a high-affinity VIP-R (kd ¼ 0.58–2.4 kd)

and a low-affinity type (kd ¼ 175–288 kd)(Fig. 2) [79]. VIP-R immunoreactivity is seen in

cystic structures of steatocystoma multiplex [80]but is absent in normal sebaceous glands [81].

Corticotropin-releasing hormone (CRH) is the

most proximal element of the hypothalamic-pitu-itary-adrenal axis, and it acts as central coordina-tor for neuroendocrine and behavioral responsesto stress. In human skin, the CRH receptor

(CRH-R) 1 is expressed in all major cellularpopulations of epidermis, dermis, and subcutiswith CRH-R1a the most prevalent isoform. The

CRH-R2 gene is expressed solely in hair folliclekeratinocytes and papilla fibroblasts, whereasCRH-R2 antigen is localized predominantly in

hair follicles, sebaceous and eccrine glands, andmuscle and blood vessels [82,83].

Investigations on the expression of CRH,CRH-binding protein (CRH-BP), and CRHRs

were performed in SZ95 sebocytes in vitro andnormal and acne-involved sebaceous glands invivo [83,84]. CRH, CRH-BP, CRH-R1, and

CRH-R2 were detectable in SZ95 sebocytes atthe mRNA and protein levels with CRH-R1the predominant type (CRH-R1/CRH-R2 ¼ 2)

(Fig. 3). CRH was biologically active on humansebocytes. It induced a biphasic increase of syn-thesis of sebaceous lipids with a maximum stimu-

lation at 10�7 Mol (M) and upregulated mRNAlevels of 3b-hydroxysteroid dehydrogenase/D(5-4)isomerase, although it did not affect cell viabil-ity, cell proliferation, or IL-1 beta-induced IL-8

release. Testosterone at 10�7 M downregulatedCRH-R1 and CRH-R2 mRNA expression at 6to 24 hours, and growth hormone switched

CRH-R1 mRNA expression to CRH-R2 at 24hours. Based on these findings, CRH may be anautocrine hormone for human sebocytes that

Fig. 2. Expression of VIP-R. Immunoperoxidase staining with VIP-R specific monoclonal antibody 109.10 (Immuno-

tech, Marseille, France) diluted 1:50. (A) Periglandular cells and cutaneous nerve fibers around the sebaceous gland

were stained whereas the sebocytes remained negative. (B) VIP-R expression in the most mature layer of epithelial cells

of steatocystoma multiplex.

583RECEPTORS OF SKIN GLANDS

Fig. 3. Expression of CRH, CRH-BP, CRH-R1, and CRH-R2 in normal human sebaceous glands. CRH barely is ex-

pressed, whereas strong expression of CRH-BP and CRH-R2 and weaker of CRH-R1 are detected. Skin biopsies were

fixed in spirit-formol (9:1) fixative for 12 hours at 4�C, rinsed in 0.01-M PBS (pH 7.6), embedded in paraffin, and sec-

tioned (2 to 3 Um thick). Sections then were heated to 60�C to melt paraffin and deparaffinized in xylene and rehydrated

for 1 minute through a graded series of ethanol. The tissue sections then were incubated with diluted 1:50 primary an-

tibodies (Santa Cruz, Heidelberg, Germany) in a humidified chamber for 30 minutes at room temperature. The optimal

concentration of both the primary and secondary antibody was predetermined by titration assay. The negative control

consisted of sections incubated with antibody diluent instead of the primary antiserum. Subsequently, the sections were

incubated with a biotinylated secondary antibody (diluted 1:500) for 15 minutes and then with a streptavidine enzyme

conjugate for 10 minutes. Finally, the sections reacted with a fuchsin substrate-chromogen system for 5–10 minutes and

counterstained with Mayer’s hematoxylin.

exerts homeostatic lipogenic activity, whereas tes-

tosterone and growth hormone induce CRH neg-ative feedback. The findings implicate CRH in theclinical development of acne, seborrhea, and otherskin disorders associated with alterations in lipid

formation of sebaceous origin [84]. AlthoughCRH does not modify the IL-6 beta-induced IL-8release, it is able todirectly enhance Il-6 and IL-8 re-

lease from human sebocytes, an activity mediatedby CRH receptors [85].

In vivo, CRH, CRH-BP, CRH-R1, and CRH-

R2 are expressed in sebaceous glands at the proteinlevel, whereas increased expression of CRH wasdetected only in acne-involved sebaceous glands[83]. The latter data indicate a proinflammatory ac-

tivity of CRH on the sebaceous gland.Adrenomedullin (AM) is a regulatory peptide

that is synthesized and secreted by a large number

of cells and tissues. AM is a potent vasodilatorand exerts other functions, such as regulating cellgrowth and antimicrobial defense. Two receptors,

L1 and calcitonin receptor-like receptor (CRLR),which are able to bind AM, have been cloned andcharacterized. Strong immunoreactivity for AM

and its receptors is present in sweat and sebaceousglands. Immunoreactivity for the CRLR revealsa similar expression pattern to that seen for AM.

AM expression is not markedly upregulated in

acne lesions, suggesting a minor role for thisantimicrobial peptide in acne. AM and its re-ceptors are colocalized in the same compartmentsand cell types of the skin. This finding is consistent

with a proposed autocrine/paracrine mechanismin the physiology of AM [86].

Sweat glands express higher levels of substance

P binding sites. Functional analysis suggests highaffinity receptors [87] Gastrin-releasing peptidereceptors have been identified in eccrine sweat

glands and sebaceous glands [88]. Somatostatinis a proinflammatory neuropeptide. The somato-statin receptor is expressed by sweat glands butnot sebaceous glands [89].

Cytokine receptors

IL-13 is involved in various chronic infectiousand in autoimmune diseases, in asthma andfibrosis [90,91]. It exerts its function after binding

to the specific IL-13 receptor (IL-13R). IL-13 hastwo types of receptor: a heterodimer, composed ofIL-13Ra1 and IL-4Ra, and the IL-13Ra2, a decoyreceptor [92].

The IL-13R is found in sebaceous glands andeccrine sweat gland of skin. It is suggested that the

584 WOLLINA et al

receptor might play a functional role in theinflammatory cascade of atopic dermatitis [93].

IL-13 and IL-13R are increased in lesional skin

of bleomycin-induced scleroderma in mice [94].Spontaneous scleroderma in humans shows a re-markable impact of skin gland architecture. It isyet not clear, however, whether or not IL-13 and

IL-13R of these glands contribute to dermal fibro-sis and sclerosis.

Cytokine receptors have been identified in

clear cells and duct epithelia of eccrine sweatglands, such as IL-1aR, IL-1bR, IL-6R, andtumor necrosis factor a-R. Inflammatory skin,

as in cutaneous leishmaniasis, shows minor mod-ifications of the staining intensity in particular forIL-6R [95].

Transforming growth factor-beta

and morphogenetic protein receptors

The transforming growth factor-beta (TGF-b)superfamily is involved in growth and differenti-ation. In mammals, TGF-b is found in threehighly homologous isoforms that exert their

effects via heteromeric complexes of type-I andtype-II receptors (TGF-b receptor proteins type Iand type II [TbRI and TbRII]). TGF-b regulates

the growth and metabolism of various cell types,

including keratinocytes. These growth factors sig-nal through transmembrane serine/threoninekinase receptors. Activation of type I receptor

kinase phosphorylates intracellular signaling pro-teins named Smads.

In normal human skin, immunoreactive TGF-b2, but not TGF-b1, is detected predominantly in

the epidermis, hair follicles, and sebaceous glands.The epidermal expression of TbRI and TbRII isvery weak in the majority of normal skin samples.

In addition, no expression of TGF-b2 is detectedin the eccrine secretory portion or in eccrinespiradenoma, but it is detected in the upper

eccrine ducts and in eccrine poroma [96].In an immunohistochemical study of human

eccrine sweat glands, expression of TGFb-RI wasrestricted to myoepithelial cells, whereas bone

morphogenetic protein-receptor (BMPR) type IAwas expressed selectively by dermal duct andacrosyringium. BMPR type IB monoclonal anti-

body gave a faint staining of secretory epitheliumand myoepithelial cells. It is suggested thatmyoepithelial cells and duct cells are major targets

of the TGF-b signaling pathway [97].The authors investigated the expression of

TGF-b1, -b2, and -b3; latent TGF-b–bindingprotein (LTBP); and TbRI and TbRII during in-duced hair growth in C57 BL-6 mice. They havefound a positive reactivity for LTBP and TbRI

Table 1

Some implications of ligand-receptor interactions of skin glands in clinical dermatology

Receptor type Pathogenic and diagnostic relevance Therapeutic relevance

Estrogen Y in eccrine neoplasms Hormone replacement therapy for menopausal

women; hormone therapy for hyperandrogenism

and female acne

Progesteron [ in syringoma ?

Androgen [ in cystic acne Dexamethasone treatment of cystic acne;

antiandrogens for female acne

Mineralocorticoid ? ?

Glucocorticoid Steroid acne ?

Orphan nuclear Acne, seborrhoea Chemoprevention of cancer

Neurotrophic factor ? ?

Vanilloid, cannabinoid,

opioid

Itch, pain Potential for new itch and pain therapy

Nicotinic/muscarinic Hyperhidrosis, pain Pain and antihydrotic therapy

Melanocortin [ in hamartomas and tumors Potential for anti-inflammatory drugs

VIP Variable expression in eccrine

tumors

?

Corticotropin-releasing

hormone

? Potential new acne treatments

Adrenomedullin ? Antimicrobial substances

IL-13 Fibrosis, sclerosis ?

TGF-b Promotes growth of sebaceous glands ?

585RECEPTORS OF SKIN GLANDS

in sebocytes. TbRII was found in sebaceousglands without significant variations during thehair cycle. A bidirectional interaction of sebocytesand hair follicle epithelium in the TGF-b/LTBPseems possible. Sebocytes can be considered tobe a target for TGFs, because they express bothTbRI and TbRII. The general properties of

TGF-b as a growth inhibitor of epithelial cellsmay suggest involvement in either the abrogationof extensive growth at the end of anagen or the

initiation of catagen for the follicle epitheliumand growth control for sebaceous glands [98].

Clinical implications and therapeutic relevance

The knowledge of specific ligand-receptor in-teractions during development and function ofskin glands not only is of academic interest but

also this knowledge has implications for diagnos-tics and treatments. The expression of ligands andreceptors is a tool in dermatopathology of adnexal

tumors. Available treatments of female acne,hyperandrogensism, focal hyperhidrosis, itch, andpain are in part based on ligand-receptor effects.Further substances and indications are on the

horizon. A summary is provided in Table 1.

Summary

The skin is the largest independent peripheralendocrine organ and exerts a great complexity ofinteraction with hormones, neuropeptides, PPARligands, growth factors, and cytokines [99,100].

Knowledge of receptor expression and receptor-ligand function offers new insight into pathologicconditions and opens new opportunities in drug

development.

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