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Hepoxilin B3 and Its Enzymatically Formed Derivative Trioxilin B3 Are Incorporated Into Phospholipids in Psoriatic Lesions

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Hepoxilin B3 and Its Enzymatically Formed Derivative Trioxilin B3 Are Incorporated Into Phospholipids in Psoriatic Lesions View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Hepoxilin B3 and its Enzymatically Formed Derivative Trioxilin B3 are Incorporated into Phospholipids in Psoriatic Lesions Rosa AntoÂn, Mercedes Camacho, LuõÂs Puig, and LuõÂs Vila Laboratory of In¯ammation Mediators, Institute of Research of the Santa Creu i Sant Pau Hospital, Barcelona, Spain In previous studies we observed that normal human position of glycerophospholipids. The thin layer epidermis forms 12-oxo-eicosatetraenoic acid (12- chromatography analysis of the phospholipid classes 14 oxo-ETE) and hepoxilin B3 (HxB3) as major eicosa- after incubation of epidermal cells with [ C]-labeled noids, both being elevated in psoriasis. We also HxB3, TrXB3, 12-hydroxy-eicosatetraenoic acid (12- observed that normal epidermis, in a reaction prob- HETE), 12-oxo-ETE, or 15-HETE showed that 12- ably catalyzed by 12-lipoxygenase, only synthesize HETE was the most esteri®ed (12-HETE > 15-HETE one of the two possible 10-hydroxy epimers of > TrXB3 > 12-oxo-ETE > HxB3). HxB3 and TrXB3 HxB3. We have now extended these previous studies were mainly esteri®ed in phosphatidyl-choline and investigating further transformation of HxB3 into phosphatidyl-ethanolamine. HxB3 was also enzyma- trioxilin B3 (TrXB3) and esteri®cation of both into tically converted into TrXB3 in vitro. HxB3 epoxide phospholipids. Phospholipids were extracted from hydrolase-like activity was not observed when boiled 14 normal epidermis and from psoriatic scales. A com- tissue was incubated with [ C]-HxB3, this activity bination of high performance liquid chromatography being located in the cytosol fraction (100,000 3 g and gas chromatography±mass spectrometry analysis supernatant) of fresh tissue. These ®ndings suggest demonstrated the occurrence of HxB3 and TrXB3 in that in vivo some part of HxB3 is transformed into the phospholipids of psoriatic lesions. Alkaline- and TrXB3 and both compounds are partially incorpor- phospholipase-A2-mediated hydrolysis of the phos- ated into the phospholipids. Key words: human epider- pholipids yielded similar quantities of both HxB3 mis/12-lipoxygenase/arachidonic acid. J Invest Dermatol and TrXB3 indicating their preference for the sn-2 118:139±146, 2002 2-Lipoxygenase (12-LO) is the major arachidonic acid HETE), normal human epidermis incubated with exogenous AA (AA) oxygenation pathway in epidermal cells with total produces 12-oxo-eicosatetraenoic acid (12-oxo-ETE), hepoxilin product formation generally exceeding cyclooxygenase A3 (HxA3), and hepoxilin B3 (HxB3) through the 12-LO pathway activity (Holtzman et al, 1989; Sola et al, 1992). Platelet- (AntoÂn et al, 1995; AntoÂn and Vila, 2000). Recently, we also 1type 12-LO has been found to be the predominant observed increased levels of nonesteri®ed hepoxilins and trioxilins isoenzyme expressed in human and murine skin epidermis in the psoriatic scales (AntoÂn et al, 1998). Normal human epidermis (Takahashi et al, 1993; Hussain et al, 1994; Krieg et al, 1995) and synthesized only one of the two possible 10-hydroxy epimers of an ``epidermal''-type 12-LO that functionally resembles the HxB3 whose formation is probably catalyzed by 12-LO (AntoÂn et platelet-type 12-LO is also present in murine epidermis (Van al, 1995; AntoÂn and Vila, 2000). Hepoxilins exert action on plasma Dijk et al, 1995; Funk et al, 1996; Kinzig et al, 1997). We previously permeability on skin (Laneuville et al, 1991; Wang et al, 1996, reported that, in addition to 12-hydroxyeicosatetraenoic acid (12- 1999a; 1999b), and induce a speci®c-receptor-dependent Ca2+ mobilization from endogenous sources (Dho et al, 1990; Laneuville et al, 1993) and the release of AA and diacylglycerol (Nigam et al, Manuscript received June 19, 2001; revised July 18, 2001; accepted for publication August 29, 2001. 1993). Interestingly, only the epimer 10(R)-HxB3, which is Reprint requests to: Dr. LuõÂs Vila, Hospital de Sant Pau, S. Antonio Ma probably the epimer synthesized by normal epidermis (AntoÂn et Claret 167, 08025-Barcelona, Spain. Email: [email protected] al, 1995; AntoÂn and Vila, 2000), stereospeci®cally enhances the Abbreviations: AA, arachidonic acid; HPETE, hydroperoxyeicosatetrae- vascular permeability evoked by intradermal injection of the noic acid; HxA3, hepoxilin A3, 8-hydroxy-11,12-epoxy-5,9,14-eicosa- platelet-activating factor (Wang et al, 1996; 1999a; 1999b). trienoic acid; HxB3, hepoxilin B3, 10-hydroxy-11,12-epoxy-5,8,14- On the other hand, less polar eicosanoids and octadecanoids, eicosatrienoic acid; LO, lipoxygenase; ME-H-TMS, hydrogenated methyl such as monohydroxy and epoxy derivatives of arachidonic and ester trimethylsilyl ether; ME-TMS, methyl ester trimethylsilyl ether; 12- linoleic acids, have been found to esterify into cell phospholipids. oxo-ETE, 12-oxo-eicosatetraenoic acid; PhC, phosphatidyl-choline; PhE, phosphatidyl-ethanolamine; PhI, phosphatidyl-inositol; PhS, phosphatidyl- Oxidized phospholipids have pro-in¯ammatory activities and are serine; RP-HPLC, reverse phase-high performance liquid chromatogra- involved in atherogenesis, psoriasis, and other in¯ammatory diseases. In human epidermis, HxB can be further converted phy; SPh, sphingomyelin; TrXA3, trioxilin A3, 8,11,12-trihydroxy-5,9,14- 3 eicosatrienoic acid; TrXB3, trioxilin B3, 10,11,12-trihydroxy-5,8,14- into trioxilin B3 (TrXB3, 10,11,12-trihydroxy-5,8,14-eicosatrie- eicosatrienoic acid. noic acid) (AntoÂn et al, 1995). As relevant biologic activity for 0022-202X/01/$15.00 ´ Copyright # 2002 by The Society for Investigative Dermatology, Inc. 139 140 ANTO N ET AL THE JOURNAL OF INVESTIGATIVE DERMATOLOGY trioxilins has not been reported (Pace-Asciak et al, 1999) these N2 atmosphere (KuÈhn et al, 1994). The reaction was stopped by adding compounds could represent a pathway for hepoxilin inactivation. 700 ml of 50 mM phosphate buffer pH = 7.4 and acidifying until pH 2± Enzymatic transformation of hepoxilins into trihydroxy compound 3. Free fatty acids were then extracted twice with 2 ml diethyl ether/ 14 was originally reported in rat lung (Pace-Asciak et al, 1983). No hexane 1:1. The reaction yield measuring release of [1± C]-AA from 1- stearoyl-2-[1±14C]-arachidonoyl-L-3-phosphatidylcholine was about 94%. data about the enzymatic metabolism of HxB3 in human epidermis are at present available, however. This prompted us to extend our For speci®c hydrolysis of the sn-2 position, phospholipid extracts were dried under an N stream, and the residue was redissolved in 10 ml of previous investigations (AntoÂn et al, 1995; 1998; AntoÂn and Vila, 2 CHCl3 and 70 ml of 30 mM borate buffer (pH = 9.0) supplemented 2000) on the presence of HxB3 in the phospholipid fraction of with 1.6 mM CaCl . The mixture was then shaken vigorously and psoriatic lesions, on HxB incorporation into the different 2 3 CHCl3 was removed under an N2 stream. 850 U of bee venom PLA2 in phospholipid classes in human epidermal cells, and on the 85 ml of 30 mM borate buffer pH 9.0 were added and the mixture was enzymatic pathways involved in the catabolism of HxB3. allowed to react for 45 min at 37°C under an N2 atmosphere with continuous agitation. Afterwards, another 850 U of PLA2 were added MATERIALS AND METHODS and allowed to react for another 100 min (Smiley et al, 1991). Reaction was stopped by acidi®cation until pH 2±3 and lipids were extracted as Materials [1±14C]-AA (55±58 mCi per mmol) was supplied by described by Bligh and Dyer (1959). After analysis of the free [14C]-AA 14 Amersham IbeÂrica (Madrid, Spain). Phospholipase A2 from bee venom released from 1-stearoyl-2-[1± C]-arachidonoyl-L-3-phosphatidylcholine was supplied by Sigma-Aldrich QuõÂmica (Madrid, Spain). Hydrated the yield of the reaction was about 96%. platinum (IV) oxide was purchased from ICN Biochemicals (Costa Mesa, Preparation of puri®ed [14C]-labeled HxB3, 12-oxo-ETE, and 12- CA). Hydrogen gas was purchased from Abello OxõÂgeno-Linde 14 HETE Labeled 12-LO-derived eicosanoids were obtained from (Barcelona, Spain). 1-Stearoyl-2-[1± C]-arachidonoyl-L-3-phosphatidyl- incubations of fragments of human epidermis, previously treated with  choline was obtained from Amersham Iberica. (6)-HxB3 were from 200 mM aspirin for 15 min, with 100 mM[14C]-AA for 30 min at 37°C, Cascade Biochem (Berkshire, U.K.). All high performance liquid and processed as described previously (AntoÂn and Vila, 2000). chromatography (HPLC) solvents were supplied by Scharlau (Barcelona, Supernatants of several incubations were mixed and processed together. Spain) and solvents for mass spectrometry analysis and N,O-bis- (trimethylsilyl)-tri¯uoroacetamide (BSTFA) were purchased from Merck Supernatants of the incubations, which had a ratio MeOH:H2O of 1:1 (Darmstadt, Germany). and a pH of 2±3, were extracted three times with half a volume of diethyl ether:hexane 1:1. Extracts were evaporated under an N2 stream Source of normal human epidermis fragments and epidermal cell until dryness, redissolved in the eluent of reverse phase high performance suspensions Epidermis was isolated from normal skin, obtained from liquid chromatography (RP-HPLC), and chromatographied as described plastic surgery, using the Liu and Karasek technique (Liu and Karasek, later. Fractions containing hepoxilins (14±20 min) and 12-oxo-ETE plus 1978) with minor modi®cations (Sola et al, 1992). Brie¯y, narrow strips 12-HETE (25±33 min) were collected and puri®ed by straight-phase of skin were cut and rinsed twice in phosphate-buffered saline, pH 7.4, HPLC as reported previously (AntoÂn et al, 1995). The speci®c activity of 2+ 2+ free of Ca and Mg (PBS*). The strips were then placed in PBS* the labeled compounds was assumed to be the same as the [14C]-AA containing 0.5% trypsin (wt/vol) (Difco Laboratories, Paisley, Scotland) batch used in their preparation as AA is labeled in the C of the carboxyl and kept at 37°C for 50±60 min.
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