Arachidonic acid metabolism in skin health and disease

Arachidonic acid metabolism in skin health and disease

Lars Iversen*, Knud Kragballe

Department of Dermatology, Marselisborg Hospital, University of Aarhus, DK-8000 Aarhus C, Denmark

1. Introduction

Arachidonic acid (AA) (eicosa-5,8,11,14-tetraenoic acid, 20:4v6) is a polyunsaturatedfatty acid with 20 carbon atoms and 4 double bounds. It is either derived from dietary sourcesor synthesized by desaturation and elongation of linoleic acid (C18:2) (Fig. 1). Because themammalian organism cannot introduce double bounds in the fatty acid structure closer to thev-end thanv9 the AA precursors linoleic acid (18:2v6) andg-linoleic acid (18:3v3) areconsidered essential [1]. AA cannot be synthesized locally in the human epidermis becauseboth d-6-desaturase andd-5-desaturase are absent in the epidermis [2]. AA present in theepidermis must therefore come from either dietary sources or it must be transported to theepidermis from other endogenous sources such as the liver, which is capable of elongationand desaturation. In the cell AA is stored in the membrane fraction, primarily esterified tophospholipids at the second carbon (sn-2) of the phospholipid glycerol backbone [3]. It isreleased from the phospholipids in the cell membrane by the action of phospholipases.

Keratinocytes respond to skin irritation and injury by a rapid but transient activation ofAA metabolism. An understanding of the enzymatic pathways involved in AA metabolismis therefore important.

2. Phospholipases

Esterified AA is not amenable to metabolic transformations. Therefore, AA has to bereleased from the cell membrane by either the phospholipase A2 (PLA2) or by a combinedaction of phospholipase C (PLC) and a diglyceride lipase. PLA2 catalyzes the hydrolysis ofthe sn-2 fatty acyl bond of phospholipids to liberate free fatty acids and either lysophos-

* Corresponding author. Tel.:145-89-49-3333; fax:145-89-49-1870.

Prostaglandins & other Lipid Mediators 63 (2000) 25–42

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pholipids or lyso-PAF depending on type of binding in the 1-position of the phospholipid(Fig. 2). The lysophospholipid may play a role in modulating or activating certain cells [4,5]and lyso-PAF may act as a precursor of platelet activating factor (PAF).

The PLA2’s are a diverse class of enzymes with regard to function, localization, regula-tion, mechanism, sequence and structure [6]. Thus, they carry out essentially the same

Fig. 1. Arachidonic acid synthesis.

Fig. 2. Phospholipase mediated processes.

26 L. Iversen, K. Kragballe / Prostaglandins & other Lipid Mediators 63 (2000) 25–42

reaction namely the hydrolysis of thesn-2 fatty acyl bond of phospholipids. Traditionallythree different human PLA2 classes have been described and characterized; the pancreaticPLA2 which is classified as digestive [7] and the two regulatory PLA2’s, the secretory (s)PLA2 [8] and the cytoplasmic (c) PLA2 [9]. Although recent evidence has revealed that thePLA2’s may be a much more diverse group of enzymes than previously believed [10] andthat the group designations will undoubtedly need to be adjusted, the designation mentionedabove will be used here.

Both the sPLA2 and the cPLA2 are present in human skin [11,12]. sPLA2’s consist of alarge isozyme family [13]. These 14 kDa isozymes are secretory enzymes and thereforemainly present extracellularly. They are devoid of specificity onsn-2fatty acid and requiremillimolar concentration of Ca21 for activation [14]. They are believed to be a key link inthe inflammatory process, e.g. as an effector system for inflammatory cytokines [15], andboth involved and un-involved psoriatic skin have been shown to contain higher levels ofsPLA2 than normal skin [11]. Several cytokines present in the skin have also been shown tomodulate the expression of sPLA2. IL-1b has been shown to induce expression and secretionof sPLA2 in a variety of cells [15], while IL-6 was shown to elevate sPLA2 levels in a humanhepatoma cell line [16]. In contrast TGF-b inhibits sPLA2 expression in rat mesangial cells[17].

cPLA2 has been purified from monocytic cell lines, U937 [18], and RAW264.7 [19], andthe cDNA coding for the enzyme was cloned from U937 cell cDNA library [20]. Themolecular weight is 85 kDa as determined by sequencing and cloning [20]. The cPLA2 istranslocated from the cytosol to the membrane fraction in a Ca21-dependent fashion [21] atphysiologically relevant Ca21 concentrations. The translocation to the membrane may be aregulatory process augmenting accessibility of the enzyme to the substrate. In contrast to thesPLA2, Ca21 does not play a catalytic role for the cPLA2, it seems only to play a role for theassociation of the enzyme with the membrane phospholipids. An interesting characteristic ofthe cPLA2 with respect to eicosanoid formation is its AA specificity [19,22], and data haveindicated that the cPLA2 is responsible for AA liberation in agonist-stimulated inflammatorycells. The involvement of AA-specific PLA2 in the production of PAF and eicosanoids from1-O-alkyl-glycerophosphocholine was suggested because both PAF and eicosanoid biosyn-thesis was abolished in polymorphonuclear leukocytes [23] and HL-60 cells [24] depleted ofAA.

The calcium requirement of PLA2 has led to speculations that PLC activation and theresulting IP3 and intracellular Ca21 elevation (Fig. 2) precede the PLA2 activation. However,several experiments have shown that PLA2 and PLC activation are regulated independentlyby different G proteins. Agonist induced AA release was shown to be sensitive to pertussistoxin treatment in mouse 3T3 fibroblasts [25] and a rat thyroid cell line, FRTL-5 [26],whereas PIP2 hydrolysis in the same cells were insensitive to toxin treatment.

In several studies PLA2 has been suggested to play an important role in inflammatory skindiseases. Intradermal injection of purified sPLA2 has been shown to induce cellular infil-tration, interstitial edema, vascular permeability and hyperemia [27]. Also, in psoriasis PLA2

has been held responsible at least in part for the elevated AA levels found, and elevated PLA2

activity has been demonstrated in psoriatic epidermis [28]. Furthermore, a recent report hasshown an increased lysophosphatidylcholine content in lesional psoriatic skin [29], support-

27L. Iversen, K. Kragballe / Prostaglandins & other Lipid Mediators 63 (2000) 25–42

ing the idea of increased PLA2 activity in inflammatory skin diseases. Investigations on howPLA2 activity is regulated have also been carried out. In the human epidermis PLA2 has beensuggested to be subject to a positive feedback regulation, as its activity was stimulated byPGE2 and PGF2a [30]. PLA2 activity may also be regulated by direct phosphorylatingactivities [31]. Furthermore, PLA2 activity may be regulated indirectly by phosphorylation-dephosphorylation of a soluble 35 kDa PLA2 inhibitory protein termed lipocortin [32]. It hasbeen suggested that upon phosphorylation, lipocortin loses its inhibitory properties, resultingin expression of PLA2 activity, and hyperphosphorylation of lipocortin has been suggestedas the reason for increased PLA2 activity in uninvolved psoriatic epidermis [33]. Also,glucocorticosteroids act by inhibition of PLA2 activity [34] via transcriptional control oflipocortin synthesis [35], and topical glucocorticosteroid application to skin results inreduction of PLA2 activity [36].

A second pathway for AA release is via breakdown of phosphatidylinositol-4,5-biphos-phate (PIP2) by the phosphoinositide-specific PLC. Hydrolysis of PIP2 generates diacylglyc-erol (DAG) and inositol-1,4,5-triphosphate (IP3) [37] (Fig. 2). DAG can be further degradedby diglyceride lipase to glycerol and free fatty acids, including AA [38] (Fig. 2). Also, PLCactivation is a primary event in intracellular signaling [39]. IP3 stimulate Ca21 mobilizationfrom intracellular stores and DAG activates protein kinase C (PKC) which orchestrates asignal transduction cascade that regulate cellular responses such as growth and differentia-tion.

PLC activity is present in most mammalian cells and tissues including human epidermis[39,40]. Epidermal PLC has been demonstrated as a Ca21 dependent enzyme with maximalactivity at pH 7.0. PLC activity in psoriatic plaque has been shown to be increased 188%compared to normal epidermis and may thus contribute to the elevated AA levels observedin this tissue [40].

At least two different mechanisms, phosphorylation of PLC by the tyrosine kinase familyand G protein-mediated PLC activation, appear to be involved in the regulation of PLCactivity [41,42]. Epidermal growth factor has been demonstrated to activate PLC by aug-menting tyrosine kinase activity [41]. The regulatory effect of tyrosine phosphorylation onPLC activity is not yet known. Increased catalytic activity due to tyrosine phosphorylationhas been reported [43], but it has also been suggested that phosphorylation increasesaccessibility of the PLC to substrate [44].

3. Cyclooxygenase

The initial step in AA metabolism by the cyclooxygenase pathway is the transformationof AA into prostaglandin H2 (PGH2) by the cyclooxygenase (COX) or PGH synthase. COXcatalyzes a two step reaction with insertion of two oxygen molecules at C11 and C15resulting in the formation of PGG2 [45]. The second step is a reductive cleavage at the15-hydroperoxy group to yield PGH2 [46]. COX is an iron containing dimer of 70 kDasubunits localized primarily in the endoplasmatic reticulum. COX is inhibited by non-steroidal antiinflammatory drugs such as aspirin and indomethacin. This inhibition largelyaccounts for the antiinflammatory and analgesic effects of these agents [47]. Recently a


second isoform of the COX has been cloned and sequenced [48,49]. The isoform designatedCOX-1 is constitutively expressed in cells whereas the isoform designated COX-2 seems torequire specific induction. In general, COX-1 regulates prostaglandin synthesis associatedwith cellular homeostasis whereas COX-2 is upregulated in inflammatory conditions andassociated with synthesis of proinflammatory prostaglandins [50]. Much attention has there-fore been paid to develop specific inhibitors of COX-2. Recently, normal murine epidermiswas found to express COX-1 but not COX-2. However, COX-2 could be induced either byacetone treatment or by topical application of the phorbol ester, TPA [51]. This is in contrastto normal human epidermis where COX-2 has been associated with keratinocyte differen-tiation [52]. In normal human skin, COX-1 immunostaining is observed throughout theepidermis whereas COX-2 immunostaining increases in the more differentiated, suprabasilarkeratinocytes [52]. Furthermore, inducing differentiation of cultured human keratinocytes byraising extracellular calcium leads to an increased expression of both COX-2 protein andmRNA. In contrast, no significant alteration in the expression of COX-1 was seen in responseto increased extracellular calcium [52]. COX-2 has also recently been implicated in thedevelopment of skin cancer [53].

PGH2 has been shown to be a central intermediate in prostaglandin biosynthesis byserving as substrate for several competing enzymes (Fig. 3). PGE synthase or PGH-PGEisomerase catalyzes the rearrangement of the endoperoxide group of PGH2 to produce PGE2.PGE synthase activity has been localized to the microsomal fraction and shown to requireglutathione as a co-factor [54]. As early as 1970 PGE2 formation in rat epidermis wasdemonstrated [55], and later rat [56] and human skin [57] were shown to synthesize PGE2.

Fig. 3. Cyclooxygenase pathway.


PGE2 is the main AA cyclooxygenase product in human epidermis homogenates [58]. PGE2

formation has also been demonstrated to be important for keratinocyte differentiation. Incultured human keratinocytes induced to differentiate by increased extracellular calcium, anincreased PGE2 formation was observed 1 h after the calcium concentration was increased[59].

PGD2 is formed from PGH2 either enzymatically or non-enzymatically. Non-enzymati-cally transformation of PGH2 into PGD2 is catalyzed by serum albumin [60]. Also twospecific enzymes, PGD synthases have been demonstrated. PGD synthases have beenlocalized as cytoplasmic enzymes unlike most other enzyme involved in prostaglandinformation which is found predominantly in the microsomal fraction [61]. PGD2 formationhas been demonstrated in human skin [58] mouse epidermis, cultured neonatal mousekeratinocytes, rat skin [62] and in guinea pig skin homogenates [63]. Interestingly PGDsynthase has been shown to be present predominantly in the Langerhans cells in guinea pigand rat epidermis and not in the keratinocytes [62,64]. Furthermore, PGD synthase wasdemonstrated in the dermal macrophages and mast cells, and generally mast cells arebelieved to represent one of the major cellular sources of PGD2.

There are three possible pathways for the synthesis of PGF2a. First by a PGF synthasefrom PGH2 (Fig. 3) [65]. Second by a reduction of PGE2 catalyzed by a NADH-linked15-hydroxy-PG dehydrogenase [66] and third from PGD2 catalyzed by a PGD 11-ketoreductase [67]. PGF2a formation has been demonstrated in both rat and human skin [68].

Thromboxane A2 (TXA2) is formed from PGH2 catalyzed by TX synthase. TXA2 isextremely unstable and therefore, rapidly transformed by a non-enzymatic process into TXB2

[69]. Only very low TXA synthase activity has been found in the skin.Prostacyclin PGI2, like TXA2 is an unstable molecule which is rapidly further metabolized

non-enzymatically into 6-keto-PGF1a. The transformation of PGH2 into PGI2 is catalyzed byPGI synthase [70]. Very low amounts of PGF1a has been found in studies of AA metabolismin guinea pig skin homogenates, indicating that PGI2 formation can take place in at leastguinea pig skin [63].

4. Lipoxygenase

The initial product of AA made by lipoxygenases (LOs) is the (mono)-hydroperoxy-eicosatetraenoic acid (HPETE) (Fig. 4). 5-, 8-, 12- and 15-LOs introduce an oxygen moleculeinto the respective position of the arachidonic acid backbone giving rise to unstable HPETEs.A HPETE undergoes reduction to its corresponding hydroxy-eicosatetraenoic acid (HETE)and under certain circumstances further oxidation to diHETEs. Among the diHETEs of the5-LO pathway are the biologically active leukotrienes (LTs).

4.1. 5-Lipoxygenase

Fig. 4 shows the metabolism of AA by the 5-LO pathway. Once AA is liberated from thephospholipids, the 5-LO is activated in the presence of ATP and Ca21 [71] and translocatedfrom the cytoplasm to the plasma membrane [72] by a Ca21 dependent mechanism.


Activated 5-LO is always membrane associated [71,73] and recently a novel membraneassociated 5-LO activating protein (FLAP) has been described [74]. FLAP has been purifiedfrom rat neutrophil membranes [74] and cloned from rat basophil leukemia cell and humanHL-60 cDNA libraries [75]. It has been identified as a 18 kDa protein [73]. So far all 5-LOexpressing cells investigated have been shown to contain FLAP. Also, transfection experi-ments have demonstrated that both FLAP and 5-LO must be present in order to transform AAinto 5-HPETE [75]. 5-HPETE is then further metabolized by the 5-LO into LTA4 [71,76] ortransformed, either enzymatically by a glutathione-dependent peroxidase or non-enzymati-cally into 5-HETE [77,78]. The transformation of AA into LTA4 results in suicide inacti-vation of the 5-LO [72].

The end product of the 5-LO activity is LTA4, an unstable allylic intermediate [79,80] thatcan be further metabolized both enzymatically and non-enzymatically. Non-enzymatically,LTA4 is metabolized into 5,6-diHETEs and 5,12-diHETEs [81]. The epoxide hydrolase,LTA4 hydrolase, catalyzes the transformation of LTA4 into LTB4 [82], and this step has beenshown to be the rate-limiting step in LTB4 formation, at least in rat basophilic leukemia cells(RBL-1) and human neutrophils [83,84].

LTA4 may also be conjugated with glutathione by LTC4 synthase to yield LTC4 [79].Successive cleavage byg-glutamyl transferase [85], and a dipeptidase [86] converts LTC4

into LTD4 and LTE4. Together LTC4, LTD4 and LTE4 are termed peptidelukotrienes.Although LTs have been ascribed an important role in inflammatory skin diseases like

psoriasis and atopic dermatitis [87–90] the capacity of the human skin itself to biosynthesizethe LTs has been questioned. It has been reported that freshly isolated human epidermal cells[91,92] and cultured mouse keratinocytes [93] can synthesize low quantities of LTB4 asdetermined by HPLC [93] and by RIA and chemotactic activity [91,92]. This view wasrecently supported by Jassen-Timmen et al. [94]. They reported that undifferentiated kera-tinocytes did not express detectable 5-LO mRNA, 5-LO protein or activity. However,

Fig. 4. 5-, 8-, 12- and 15-lipoxygease pathways.


inducing differentiation by shifting the culture conditions resulted in induction of 5-LO geneexpression. Thus, the induction of 5-LO expression was much more pronounced in keratin-ocytes derived from the HaCat cell line than in normal human keratinocytes. In contrast, inthe study by Brenton et al. [95] measurements of 5-LO protein determined by Western blotsor 5-LO mRNA determined by reverse transcriptase polymerase chain reaction (PCR)analysis in cultured human keratinocytes treated with either IL-1, 1,25-vitamin D3, interfer-on-g, PMA, A23187 or dexamethason did not demonstrate the presence of 5-LO in humankeratinocytes. Furthermore, FLAP was not present in subcellular fractions of these keratin-ocytes consistent with the absence of FLAP mRNA in these cells. The lack of 5-LO is inaccordance with previous reports from our laboratory [96–98] and others [99] showing nodetectable LTB4 formation in normal human cultured keratinocytes stimulated with A23187and in freshly isolated human epidermis. It is therefore likely, that the 5-LO activity in thehuman keratinocytes is very limited.

4.1.1. Transcellular leukotriene synthesisAlthough the epidermis cannot form leukotrienes itself from AA, it can contribute

significantly to leukotriene formation through transcellular leukotriene synthesis. By thismechanism, LTA4 formed in one cell type is released and then further metabolized in anothercell type (Fig. 5). Human cultured keratinocytes and human epidermis has been shown totransform neutrophil derived LTA4 into LTB4 in vitro [96–99]. The key enzyme in trans-cellular LTB4 formation in the epidermis is the LTA4 hydrolase (Fig. 5). The LTA4hydrolase has been localized in the human epidermis by activity determination [96–99], byinhibition of enzyme activity by bestatin and captopril (known LTA4 hydrolase inhibitors)[96–98], by Western blotting [98] and by immunohistochemical staining [100]. Furthermore,the LTA4 hydrolase has been purified and characterized from cultured human keratinocytesand human epidermis [101]. The epidermal LTA4 hydrolase was characterized as a 70 kDaenzyme, with a pI of 5.1–5.4, a pH optimum of 7.5–8.5 and it was localized in thecytoplasmic fraction [98]. The amino acid composition has been determined and all the dataobtained from human epidermis and cultured human keratinocytes have been consistent withdata obtained with LTA4 hydrolase from most other cell types that have been investigated[101]. An interesting characteristic of the LTA4 hydrolase is that it has a dual function

Fig. 5. Transcellular leukotriene synthesis.


exhibiting both hydrolase activity as well as peptidase activity. Peptidase activity has beenshown against small peptides including opioids [102,103]. Another characteristic feature ofthe LTA4 hydrolase is that it undergoes suicide inactivation when it transforms LTA4 intoLTB4. This has been demonstrated in several cell types [104] including human epidermis[100] and is due to covalent binding of LTA4 to the enzyme [105]. Presumably, as a resultof suicide inactivation, the LTA4 hydrolase has been shown as the rate limiting step in LTB4

formation at least in human neutrophils [84] and rat basophilic leukemia cells [83]. There-fore, transcellular LTA4 metabolism may result in an increased LTB4 formation at aninflammatory site. In inflammatory skin diseases like psoriasis, neutrophils migrate into theepidermis and get into close contact with the keratinocytes. Release of LTA4 into theextracellular space has previously been demonstrated by activated neutrophils, and veryrecently it was demonstrated that more than 50% of the LTA4 formed in neutrophils isreleased from the cell [106]. Transcellular leukotriene synthesis may therefore be an impor-tant mechanism by which the human epidermis can contribute significantly to LTB4 forma-tion in inflammatory skin diseases.

Similar to transcellular LTB4 synthesis, transcellular LTC4 synthesis has been demon-strated as a possible mechanism for LTC4 formation in the epidermis [97] (Fig. 5). LTA4 istransformed into LTC4 by a LTC4 synthase (Fig. 4), which in mouse mastocytoma cells hasbeen shown as a highly specific, membrane bound glutathione-S-transferase (GST) [107]. Inthe skin a specific LTC4 synthase has, however, never been shown. Several isoforms of GSTwith activity toward LTA4 have been identified in human and rodent skin [108], and human,rat and mouse skin has been demonstrated to transform LTA4-methyl ester into LTC4-methylester [109].

4.2. 8-Lipoxygenase

The 8-LO is one of the most recent discovered LOs in the skin. 8-LO activity is bestcharacterized in tissue samples from marine sources [110]. Only brief reports have beenpublished on the enzymatic production of 8-HETE in human tissues and cell types such ashuman leukocytes [111], human tracheal cells [112] and psoriatic skin [113]. However,recently 8-LO activity in mouse skin has been determined and characterized [114,115]. Theepidermal 8-LO was shown as a specific 8(S)-LO catalyzing the formation of only 8(S)-HPETE and 8(S)-HETE [114]. However, recently varying S to R ratios of 8-HETE in miceskin has been shown [116] indicating that in addition to 8(S)-LO other enzymes yet to bedefined may be involved in 8-HETE production. Enzyme activity was localized in thecytosolic fraction of the cells in the suprabasal compartment of the epidermis [115] andactivity was stimulated by phosphatidylcholine and lecithin whereas no requirement of ATP,calcium or NADPH was found [114,115]. In contrast to the 5-LO, 8-LO is not translocatedto the membrane when it is activated. Interestingly, only very low 8-LO activity has beendetermined in normal mouse epidermis indicating that the enzyme is not constitutivelyexpressed in the epidermis. However, a prominent dose-dependent induction of 8-LO activityhas been demonstrated in mouse epidermis after topical treatment with TPA [115]. Inter-estingly, mouse skin 8-LO has also been shown to exhibits leukotriene A synthase activitywhen incubated with 5-HPETE [117], and in contrast to a linear time course of the 8-LO


reaction with AA, leukotriene A synthase activity seems to undergo suicide inactivation[117]. These data together with the fact that 8-HETE is present in psoriatic skin [113] suggestsome pathophysiological function of the 8-LO pathway in the skin. Interestingly, it hasrecently been reported that 8(S)-HETE is a high affinity ligand for the peroxisome prolif-erator-activated receptora (PPARa) whereas 8(R)-HETE was much less potent [118,119].PPARs are members of the nuclear receptor superfamily that includes receptors for thesteroid, thyroid and retinoid hormones. Through dimerization of the PPAR with the 9-cis-retinoic acid receptor (RXR) and activation of a PPAR response element, transcription ofspecific genes are regulated. It can be speculated that this is a possible pathway by which8(S)-HETE exerts some of its possible pathophysiological effects in the skin. It is certainlyan area which deserves further investigation in the future.

4.3. 12-Lipoxygenase

12-HETE has been shown as one of the main eicosanoids formed by the epidermis [58],and with the discovery of large quantities of 12-HETE in human psoriatic lesions [58,120]the epidermal 12-LO has gained considerable interest. 12-LO activity results in the formationof 12-HPETE, which is reduced to 12-HETE. The reduction of 12-HPETE involves aglutathione-dependent peroxidase [121]. The 12-LO has been partially characterized inmouse [122,123], human [58,124], rat [124,125] and guinea pig [126] epidermis andkeratinocytes [93]. Furthermore, recently cDNA cloning of mouse epidermal 12-LOs hasbeen carried out [123]. Both a cytosolic and a microsomal 12-LO was identified [123,127].The cytoplasmic 12-LO is also termed the leukocyte type lipoxygenase whereas the micro-somal 12-LO is termed the platelet type. The platelet-type 12-LO metabolizes AA exclu-sively into 12-HETE whereas the leukocyte-type 12-LO transforms AA into both 12-HETEand 15-HETE [123]. In normal human and mouse epidermis as well as involved psoriaticepidermis and cultured human keratinocytes only the platelet-type 12-LO is detectable(mRNA and antibodies against the protein) [123,128,129]. However, in mouse epidermisboth isozymes were induced transiently by phorbol esters [123]. The leukocyte-type 12-LOthat is induced by phorbol ester treatment has been suggested to originate from Langerhanscells [123]. In mice the platelet-type 12-LO has been localized to the stratum granulosum byimmunohistochemical analysis [130]. Both the platelet-type 12-LO and the leukocyte-type12-LO specifically result in the formation of 12(S)-HETE [123,131]. It is therefore of interestthat the 12-HETE in psoriatic scale is not the expected lipoxygenase derived 12(S)-HETE butinstead consists predominantly of 12(R)-HETE [132]. This stereochemical difference mayindicate that 12-HETE is synthesized by different enzymes. For example, cytochrome P-450monooxygenases have been reported to produce predominantly 12(R)-HETE rather than12(S)-HETE from AA [133,134]. Whether 12(R)-HETE recovered from psoriatic lesions isformed by the cytochrome P-450 system has not yet been clarified.

4.4. 15-Lipoxygenase

The initial step of the 15-LO pathway is oxygenation of AA at C-15 resulting in theformation of 15-HPETE, which can either be reduced by glutathione peroxidase to the


corresponding 15-HETE or converted to 14,15-LTA4 by the action of LTA synthase.14,15-LTA4 is then transformed into 5,15-diHETE, isomers of 8,15-diHETE and isomers of14,15-diHETE [135,136]. Alternatively, 5,15-diHETE can be formed in a reaction catalyzedby 5-LO, because 15-HETE can act as substrate for 5-LO leading to the formation of5,15-diHETE [137]. The 15-LO has been shown to be a Ca21-dependent enzyme localizedpredominantly in the cytosolic fraction [138]. 15-HETE formation may be increased byendogenous HETEs [139] and 15-HETE itself has been shown as a potent activator of itsown formation. Because 15-HETE is a potent 5-LO inhibitor [140], the increased formationof 15-HETE is most likely caused by inhibition of 5-LO resulting in increased substrateavailability for the 15-LO pathway.

The 15-LO has been shown to be present in a variety of tissues including human skin[141] and human keratinocytes [142].

However, several careful studies have revealed rather conflicting data regarding 15-LOactivity in human epidermis. 15-HETE was identified as the only mono-HETE formed bycultured human keratinocytes by several different groups [142–144] whereas others havefound 12-HETE as the prominent AA-metabolite produced by homogenous suspensions offreshly isolated epidermal cells, with only low amounts of 15-HETE present [93,145].Recently these differences have been explained by the various techniques used to isolate thekeratinocytes and the epidermis. It has been demonstrated that AA-metabolism by humankeratinocytes depends upon their functional differentiation. 12-HETE is mainly formed bythe upper epidermal layers whereas 15-HETE is formed predominantly by the basal kera-tinocytes [146].

5. Catabolism of leukotrienes

For cellular homeostasis and for limiting the pro-inflammatory effects of leukotrienes it isessential that the generated leukotrienes in the skin are catabolized to less biologically activecompounds. The metabolism of LTB4 differs among tissues. In human epidermis LTB4 ismetabolized by anv-oxidation pathway into 20-hydroxy-LTB4 and 20-carboxy-LTB4 [147,148]. The first step of inactivation is the conversion of LTB4 into 20-hydroxy-LTB4 throughthe action of a NADPH-dependent microsomal cytochrome p-450 [147,149]. The secondstep is oxidation of 20-hydroxy-LTB4 into 20-carboxy-LTB4 by an aldehyde dehydrogenase.Both 20-hydroxy-LTB4 and 20-carboxy-LTB4 are at least 10-times less potent than LTB4 ininducing chemotaxis of guinea pig peritoneal eosinophils and neutrophils [150]. In culturedhuman keratinocytes LTB4 has also been shown to be metabolized by a 12-hydroxydehy-drogenase resulting in the formation of 12-oxo-LTB4 which is further metabolized intovarious dihydro-LTB4 metabolites [151]. The LTB4 12-hydroxydehydrogenase has beenpurified to homogeneity from porcine kidney cytosol [152] and very recently cDNA cloningof porcine and human LTB4 12-hydroxydehydrogenase has been carried out [153]. 12-oxo-LTB4 has been shown to be at least 100-times less potent than LTB4 in increasing intracel-lular calcium [154].

Metabolic inactivation of the peptideleukotrienes are thought to result from the transfor-


mation of LTC4 to LTD4 and LTE4. However, both LTD4 and LTE4 have potent biologicactivities depending upon the biologic system studied.

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Arachidonic acid metabolism in skin health and disease

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