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(2010) do raise the interesting question as role of hBD-2 in adaptive immunity are Harder J, Bartels J, Christophers E et al. (1997) A to how the presence of other AMPs, needed before it is dismissed in relation peptide antibiotic from human skin. Nature 387:861 which apparently have good direct anti- to the skin infections in AD. Harder J, Dressel S, Wittersheim M et al. (2010) S. aureus activity, is incapable of con- Enhanced expression and secretion of anti- trolling skin infections in AD. CONFLICT OF INTEREST microbial peptides in atopic dermatitis and Although recent studies have focused The author states no conflict of interest. after superficial skin injury. J Invest Dermatol 130:1355–64 on the regulation of AMPs by adaptive Peck Y. Ong1,2 Henseler T, Christophers E (1995) Disease con- immunity, it is not clear how the 1 Division of Clinical Immunology and Allergy, comitance in psoriasis. J Am Acad Dermatol relatively high expression of IL-22, a Children’s Hospital Los Angeles, Los Angeles, 32:982–6 California, USA and 2Department of Pediatrics, key cytokine of adaptive immunity that Jansen PA, Rodijk-Olthuis D, Hollox EJ et al. Keck School of Medicine, University of regulates AMPs, does not appear to (2009) Beta-defensin-2 protein is a serum Southern California, Los Angeles, California, USA biomarker for disease activity in psoriasis and upregulate hBD-2 level in AD (Wolk E-mail: [email protected] et al., 2004). hBD-2 has led the way in reaches biologically relevant concentrations in lesional skin. PLoS One 4:e4725 studies of AMPs’ effects on adaptive Lowes MA, Kikuchi T, Fuentes-Duculan J et al. immunity (Yang et al., 1999). It binds REFERENCES (2008) Psoriasis vulgaris lesions contain and attracts cells expressing the chemo- David TJ, Cambridge GC (1986) Bacterial infection discrete populations of Th1 and Th17 T cells. kine receptor, CCR6 (Ro¨hrl et al., 2010). and atopic eczema. Arch Dis Child 61:20–3 J Invest Dermatol 128:1207–11 A significant proportion of CCR6-expres- de Jongh GJ, Zeeuwen PL, Kucharekova M et al. Ong PY, Leung DYM (2002) The chemokine receptor CCR6 identifies interferon-gamma sing T helper cells also produce IFN-g,IL- (2005) High expression levels of keratinocyte expressing T cells and is decreased in atopic antimicrobial proteins in psoriasis compared 17, and/or IL-22 (Ong and Leung, 2002; dermatitis as compared with psoriasis. with atopic dermatitis. J Invest Dermatol Duhen et al., 2009). The increased and J Invest Dermatol 119:1463–4 125:1163–73 decreased expression of IFN-g/IL-17 in Ong PY, Ohtake T, Brandt C et al. (2002) Endogenous psoriatic and AD lesions, respectively Duhen T, Geiger R, Jarrossay D et al. (2009) antimicrobial peptides and skin infections in Production of interleukin 22 but not inter- atopic dermatitis. NEnglJMed347:1151–60 (Lowes et al., 2008) (Guttman-Yassky leukin 17 by a subset of human skin-homing Ro¨hrl J, Yang D, Oppenheim JJ et al. (2010) et al., 2008), are not inconsistent with memory T cells. Nat Immunol 10:857–63 Specific binding and chemotactic activity of the ability of hBD-2 to drive adaptive Gambichler T, Skrygan M, Tomi NS et al. (2008) mBD4 and its functional orthologue hBD2 to immunity against skin infections. How- Differential mRNA expression of antimicro- CCR6 expressing cells. J Biol Chem 285: ever, this hypothesis needs to be verified bial peptides and proteins in atopic derma- 7028–34 further. As a proportion of AD patients are titis as compared to psoriasis vulgaris and Wolk K, Kunz S, Witte E et al. (2004) IL-22 not affected by skin infections (David and healthy skin. Int Arch Allergy Immunol increases the innate immunity of tissues. 147:17–24 Cambridge, 1986), it may be of interest to Immunity 21:241–54 Guttman-Yassky E, Lowes MA, Fuentes-Duculan J evaluate whether there is any correlation Yang D, Chertov O, Bykovskaia SN et al. (1999) et al. (2008) Low expression of the IL-23/ Beta-defensins: linking innate and adaptive between hBD-2 level and clinical infec- Th17 pathway in atopic dermatitis compared immunity through dendritic and T cell CCR6. tion in AD. Further studies on the exact to psoriasis. J Immunol 181:7420–7 Science 286:525–8

Origin of 7-Dehydrocholesterol (Provitamin D) in the Skin

Journal of Investigative Dermatology (2010) 130, 2139–2141; doi:10.1038/jid.2010.118; published online 6 May 2010

TO THE EDITOR tion of cholesterol from food or bile to (10th) edition of a German Pharmacol-

Bogh et al. (2010) recently found that pro-vitamin D3 (7-dehydrocholester- ogy textbook (Flockerzi, 2009). the increase in 25-(OH)-hydroxychole- ol),whichisthentransportedtothe Although we have no access to the calciferol (25-(OH)-D) after UV-B ex- skin, mainly the epidermis, wherein it cited textbook of Champe et al. (2005),

posure in 28 non-sun-worshippers was is isomerized to pre-vitamin D3 in the textbook by Rang et al. (1995), positively correlated with baseline total (cholecalciferol) by UVB radiation one can find on page 449: cholesterol levels. In their discussion of (Champe et al., 2005). Cholecalciferol (D ) generated in the this interesting observation, the authors 3 A similar statement (regarding the skin from 7-dehydrocholesterol by cite from a biochemistry textbook: formation of 7-dehydrocholesterol in the action of ultraviolet radiation, The synthesis of vitamin D starts in the intestine and its transport to the the 7-dehydrocholesterol having the bowel epithelial with the oxida- skin) is on page 732 in the most recent been formed from cholesterol in the wall of the intestine.

Abbreviations: DHCR7, D-7-sterol reductase; HDL, high-density lipoprotein; HMG-CoA, A biochemistry textbook (Campbell hydroxymethylglutaryl-CoA; LDL, low-density lipoprotein; 25-(OH)-D, 25-(OH)-hydroxycholecalciferol and Farrell, 2009) shows in Figure 8.30

www.jidonline.org 2139 HH Glossmann Origin of 7-Dehydrocholesterol

Acetyl-CoA readers on the origin of the precursor for vitamin D in the skin (Figure 1). The Multiple steps last step in cholesterol biosynthesis requires enzymatic reduction of the D-7 double bond of 7-dehydrocholesterol Squalene by a D-7-sterol reductase (DHCR7). The human DHCR7 (EC 1.3.1.21) was first Multiple steps cloned and functionally expressed by Moebius et al. (1998). The enzyme, which is abundant, for example, in the Lathosterol liver, requires NADPH as a proton donor and NADH cannot substitute. Lathosterol-5-desaturase DHCR7 contains putative sterol-sensing domains (Bae et al., 1999). Any 7-Dehydrocholesterol 7-dehydrocholesterol originating from (provitamin D) the gut would be rapidly converted to cholesterol in the liver, never reaching AY 9944 7-Dehydrocholesterol reductase Cholesterol the systemic circulation. A physiologi- cally occurring backward reaction from cholesterol to 7-dehydrocholesterol, Cholesterol catalyzed by either D-7-sterol reductase Figure 1. Cholesterol biosynthesis in keratinocytes and provitamin D. Differentiated keratinocytes must or another enzyme, to the best of our synthesize cholesterol de novo starting from acetyl-CoA. When squalene is formed, the first sterol intermediate, knowledge, has never been reported, all subsequent steps occur in the endoplasmic reticulum, the steroid being transferred from enzyme to enzyme unless Figure 2 and Table 9 in Glover without leaving the membrane phase. The two last steps in the multiple-reaction pathway are shown. et al. (1952) are accepted as solid proof. A 5-desaturase (EC 1.3.3.2) catalyzes the insertion of a double bond into lathosterol (5-a-cholest-7en-3b-ol), yielding 7-dehydrocholesterol (cholesta-5,7dien-3bol) ¼ provitamin D. D-7-Sterol reductase (DHCR7) converts It may have escaped some of the provitamin D into cholesterol. Two inhibitors (AY-9944 and BM15.766) are often used to decrease the DHCR7 textbooks that the epidermis is a very activity experimentally in cell culture or in animals and thereby increase the concentration of provitamin D. active site of de novo cholesterol bio- Increased import of cholesterol by keratinocytes may also slow down DHCR7 activity. synthesis. Differentiated keratinocytes have lost low-density lipoprotein (LDL) receptors, but not high-density lipo- protein (HDL) receptors (see Feingold on page 224 an enzymatic reaction that ing) cholesterol to 7-dehydrocho- (2009) and the references cited herein). catalyzes the formation of 7-dehydro- lesterol; They must synthesize sufficient choles- cholesterol from cholesterol. In the b. 7-dehydrocholesterol is then trans- terol for export through lamellar bodies paper by Pe´rez-Castrillo´n et al., 2007, ported to the skin via the blood- and a functioning lipid barrier. As each one can read on page 905: stream; molecule of cholesterol originates from c. inhibition of the hydroxymethyl- its precursor, 7-dehydrocholesterol, the Inhibition of the enzyme [i.e.: HMG- glutaryl-CoA (HMG-CoA)-reductase circulating 7-dehydrocholesterol cannot CoA reductase] may increase levels by statins increases the levels of have a significant role in the formation of 7-dehydrocholesterol and in- 7-dehydrocholesterol. of vitamin D. The human skin gradient crease the synthesis of 25-(OH)- of 7-dehydrocholesterol increasing from hydroxycholecalciferol. In Goodman&Gilman’s 11th edition the dermis to the stratum spinosum (Friedman, 2006), however, on page (Holick et al., 1980) also argues for this This is cited by Bogh et al. (2010) as 1652, one reads: conclusion. follows: Levels of 7-dehydrocholesterol in Statin therapy inhibits the enzyme Ultraviolet irradiation of several ani- the serum of healthy individuals are mal and plant sterols results in their hydroxymethylglutaryl-CoA (HMG- around 0.3 mM and are apparently CoA) reductase (Champe et al., conversion to compounds possessing directly correlated with the activity of 2005), which is believed to increase vitamin D activity. The principal the HMG-CoA-reductase activity of the the level of 7-dehydrocholesterol, a provitamin found in animal tissues is liver (Axelson et al., 1998; de Sain-van precursor of vitamin D. 7-dehydrocholesterol, which is der Velden et al., 2008). Thus, statins synthesized in the skin [emphasis by may decrease, but not increase, the Taken together, these statements us]. Exposure of the skin to sunlight level of circulating 7-dehydrocholester- claim that converts 7-dehydrocholesterol to cho- ol. This view is supported by cell y a. there is an enzymatic reaction, lecalciferol (vitamin D3)[ ]. culture experiments in which simvasta- occurring in the intestine wall or We agree with the latter authors and tin treatment increased the expression bowel epithelia, converting (oxidiz- will take the opportunity to inform the of genes involved in cholesterol synth-

2140 Journal of Investigative Dermatology (2010), Volume 130 JW Fluhr et al. Role of Histidase in SC Acidification

esis, including the D-7-sterol reductase Bae SH, Lee JN, Fitzky BU et al. (1999) Starke K, eds). Mu¨nchen: Urban & Fischer, (Wassif et al., 2005). Cholesterol biosynthesis from Lanosterol 732 [y]. J Biol Chem 274:14624–31 In summary, the data of Bogh et al. Friedman PA (2006) In: Goodman&Gilman’s Bogh MK, Schmedes AV, Philipsen PA et al. The Pharmacological Basis of Therapeutics. (2010) extend earlier observations of (2010) Vitamin D production after UVB 11th ed. (Brunton LL, ed). New York: the relationship between LDL to HDL exposure depends on baseline vitamin D McGraw-Hill, 1652 ratios and 25-(OH)-D (Carbone et al., and total cholesterol but not on skin pigmen- Glover M, Glover J, Morton RA (1952) Provitamin 2008). This points to a relationship tation. J Invest Dermatol 130:546–53 D3 in tissues and the conversion of choles- Campbell MK, Farrell SO (eds) (2009) Biochem- terol to 7-dehydrocholesterol in vivo. Bio- between systemic HDL and LDL cho- chem J 51:1–9 lesterol levels and DHCR7 activity in istry. 6th ed. Belmont: Thomson Brooks/Cole, 224 Holick MF, MacLaughlin JA, Clark MB et al. keratinocytes, perhaps via the sterol- Carbone LD, Rosenberg EW, Tolley EA et al. (1980) Photosynthesis of previtamin D3 in human skin and the physiologic conse- sensing domain of the enzyme. (2008) 25-Hydroxyvitamin D, cholesterol, quences. Science 210:203–5 and ultraviolet irradiation. Metabolism CONFLICT OF INTEREST 57:741–8 Moebius FF, Fitzky BU, Lee JN et al. (1998) Molecular cloning and expression of the The author states no conflict of interest. Champe PC, Harvey RA, Ferrier DR (eds) human delta7-sterol reductase. Proc Natl 1 (2005) Biochemistry. 3rd ed. Philadelphia: Hartmut H. Glossmann Acad Sci USA 95:1899–902 Lippincott Williams and Wilkins, 534 1Institut fu¨r Biochemische Pharmakologie, Pe´rez-Castrillo´n JL, Vega G, Abad L et al. (2007) de Sain-van der Velden MG, Verrips A, Prinsen Medizinische Universita¨t Innsbruck, Innsbruck, Effects of Atorvastatin on vitamin D levels in BH et al. (2008) Elevated cholesterol pre- Austria. E-mail: [email protected] patients with acute ischemic heart disease. cursors other than cholestanol can also be a Am J Cardiol 99:903–5 hallmark for CTX. J Inherit Metab Dis; e-pub Rang HP, Dale MM, Ritter JM (eds) (1995) ahead of print 24 October 2008 REFERENCES Pharmacology. 3rd ed. Edinburgh: Churchill Feingold KR (2009) The outer frontier: the Livingstone, 449 Axelson M, Angelin B, Hillebrant CG et al. (1998) importance of lipid metabolism in the skin. Wassif CA, Krakowiak PA, Wright BS et al. (2005) J Lipid Res 50(Suppl):S417–22 The level of 7-dehydrocholesterol in plasma Residual cholesterol synthesis and simvasta- reflects the activity of 3-hydroxy-3-methyl- Flockerzi V (2009) In: Allgemeine und spezielle tin induction of cholesterol synthesis in glutaryl coenzyme A reductase in the human Pharmakologie und Toxikologie. 10th ed. Smith-Lemli-Opitz syndrome fibroblasts. liver. Biochim Biophys Acta 1394:153–7 (Aktories K, Fo¨rstermann H, Hofmann F, Mol Genet Metab 85:96–107

Is the Filaggrin–Histidine–Urocanic Acid Pathway Essential for Stratum Corneum Acidification?

Journal of Investigative Dermatology (2010) 130, 2141–2144; doi:10.1038/jid.2010.74; published online 8 April 2010

TO THE EDITOR and the moist interior of the body (Elias, of the SC increases, the metabolism of Acidification of the surface of the 2007). This permeability barrier resides glucosylceramides and sphingomyelin stratum corneum (SC), the acid mantle, in the extracellular lipid membranes of to ceramides is impaired, resulting was initially thought to be important the SC, and studies have shown that an in abnormal permeability barrier home- in the defense against infection. The acidified SC is required for the forma- ostasis (Holleran et al., 1992, 1993; growth of pathogenic microorganisms, tion of a functionally competent perme- Feingold, 2007). In addition, an acidic such as Staphylococcus aureus and ability barrier (Mauro et al., 1998; Fluhr SC pH inhibits the activity of serine Streptococcus pyogenes, is inhibited et al., 2001; Hachem et al., 2003). proteases thereby maintaining the by an acidic skin pH whereas the Specifically, in the SC b-glucocerebro- cohesiveness and integrity of the SC growth of resident (normal) skin flora sidase and acid sphingomyelinase (Hachem et al., 2005). With an increase is stimulated (Puhvel et al., 1975; metabolize glucosylceramides and in SC pH, the activities of these serine Korting et al., 1990, 1992). However, sphingomyelin, respectively, to cera- proteases are stimulated resulting in the recent studies have shown that acidifi- mides, which is the major family of degradation of corneodesmosomes and cation of the SC has additional func- lipids in the extracellular membranes a decrease in SC integrity and cohesion tions, including regulating several that mediate permeability barrier func- (Fluhr et al., 2004b; Hachem et al., key SC functions. A major function of tion (Feingold, 2007). Both the enzymes 2005). Thus, an acidic SC is important the skin is to form a permeability barrier require an acidic milieu for optimal in regulating the metabolism and func- between the dry external environment enzymatic activity; hence, when the pH tion of the SC, and alterations in SC pH could have numerous adverse effects. A variety of different pathways are Abbreviation: SC, stratum corneum postulated to contribute to the acid mantle

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