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Transcellular Biosynthesis of Cysteinyl Leukotrienes in Vivo During Mouse Peritoneal Inflammation

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Transcellular Biosynthesis of Cysteinyl Leukotrienes in Vivo During Mouse Peritoneal Inflammation Transcellular biosynthesis of cysteinyl leukotrienes in vivo during mouse peritoneal inflammation Simona Zarini1, Miguel A. Gijo´ n1, Aaron E. Ransome, Robert C. Murphy2, and Angelo Sala3 Department of Pharmacology, University of Colorado Denver, Mail Stop 8303, 12801 East 17th Avenue, Aurora, CO 80045 Communicated by K. Frank Austen, Brigham and Women’s Hospital, Boston, MA, April 7, 2009 (received for review February 23, 2009) Leukotrienes (LTs) are lipid mediators of inflammation formed by leukotriene B4 (LTB4). LTC4 can be metabolized by sequential enzymatic oxidation of arachidonic acid. One intriguing aspect of proteolytic hydrolysis to leukotriene D4 (LTD4) and leukotriene LT production is transcellular biosynthesis: cells expressing 5- E4 (LTE4); these 3 compounds are collectively termed cysteinyl lipoxygenase (5LO) form LTA4 and transfer it to cells expressing LTs (cysLTs). The final LT products derived from LTA4 play LTA4 hydrolase (LTA4H) or LTC4 synthase (LTC4S) to produce LTB4 or important roles in inflammation, such as inducing neutrophil LTC4. This process has been demonstrated in vivo for LTB4, but not chemotaxis (LTB4) or causing edema and smooth muscle con- for cysteinyl LTs (cysLTs). We examined transcellular cysLT synthe- traction (LTC4, LTD4) (1, 2). The effects of these eicosanoids are sis during zymosan-induced peritonitis, using bone marrow trans- mediated by G-protein coupled receptors. Two have been iden- plants with transgenic mice deficient in key enzymes of LT syn- tified for LTB4 (BLT1 and BLT2) (13, 14), and 3 for cysLTs thesis and analyzing all eicosanoids by liquid chromatography/ (cysLT1, cysLT2, and GPR17) (15–17). Although the protein has tandem mass spectrometry. WT mice time-dependently produced not been identified, a novel receptor showing specificity for ؊/؊ LTB4 and cysLTs (LTC4, LTD4, and LTE4). 5LO mice were incapable LTE4 has been recently described (18). CysLT1 receptor antag- of producing LTs. WT bone marrow cells restored this biosynthetic onists are currently used to help control asthma symptoms, and ability, but 5LO؊/؊ bone marrow did not rescue LT synthesis in drugs that interfere with LT biosynthesis or action are candidates irradiated WT mice, demonstrating that bone marrow-derived cells for preventing cardiovascular disease (19, 20). are the ultimate source of all LTs in this model. Total levels of LT production is regulated at different levels (8), including ؊/؊ 5LO-derived products were comparable in LTA4H and WT mice, methylation of the 5LO promoter (21) and posttranslational ؊/؊ IMMUNOLOGY but were reduced in LTC4S animals. No differences in prosta- control of 5LO activity through phosphorylation, interaction glandin production were observed between these transgenic or with FLAP (11, 12), and translocation induced by calcium or free ؊/؊ ؊/؊ chimeric mice. Bone marrow cells from LTA4H or LTC4S mice AA (22). Additionally, experimental evidence suggests that cells ؊/؊ injected into 5LO mice restored the ability to synthesize LTB4 cooperate in the synthesis of LTB4 and LTC4. For example, and cysLTs, providing unequivocal evidence of efficient transcel- human platelets, which express no 5LO, can interact with lular biosynthesis of cysLTs. These results highlight the potential activated neutrophils, which do not express LTC4S, to generate relevance of transcellular exchange of LTA4 for the synthesis of LTs LTC4 (23). Many other instances of transcellular LT biosynthesis mediating biological activities during inflammatory events in vivo. have been described (24). The chemical half-life of LTA4 in buffer is less than 5 s (25), which implies some protective chimeric mice ͉ leukotriene B4 ͉ mass spectrometry ͉ leukotriene E4 ͉ mechanism of the epoxide ring during transfer from the donor 5-lipoxygenase cell to the acceptor cell. Mice deficient in enzymes responsible for LT synthesis are eukotrienes (LTs) are biologically active lipid mediators that valuable tools to test the extent of transcellular formation of LTs. Koller and colleagues illustrated this value by transplanting bone Lplay important roles in inflammation and are involved in Ϫ/Ϫ Ϫ/Ϫ pathological states with an inflammatory component, such as marrow from LTA4H mice into lethally irradiated 5LO asthma, cardiovascular disease, or cancer (1–5). They derive mice (26). In a peritoneal inflammation model, LTB4 was found from arachidonic acid (AA) through the action of 5-lipoxygen- to be synthesized, proving that transcellular biosynthesis did ase (5LO) (6), an enzyme expressed in a limited number of cells, occur in vivo. Production of LTB4 in these chimeric animals was significantly lower than in WT controls or 5LOϪ/Ϫ mice rescued including neutrophils, eosinophils, monocytes, macrophages, with WT bone marrow. This raised questions about the extent of mast cells, and basophils (7, 8). Considerable work has led to our transcellular biosynthesis, whether this was a minor pathway for current understanding of events regulating the formation of in vivo LT generation, or whether LTA was converted into other these mediators. AA is released from phospholipids by cytosolic 4 products besides LTB . phospholipase A ␣ (cPLA ␣) after this enzyme translocates 4 2 2 In the present study, our main aim was to find evidence of the from cytosol to perinuclear membranes of cells, usually following possible transcellular biosynthesis of cysLTs using LTC SϪ/Ϫ an increase in calcium ion concentration (9). 5LO, a soluble 4 bone marrow cells, while identifying and quantifying all of the protein in the cytosol or nucleoplasm of resting cells, also major COX- and 5LO-derived eicosanoids. translocates to perinuclear membranes when calcium levels increase (10). 5LO oxidizes free AA to 5-hydroperoxyeicosatet- Results raenoic acid. This intermediate can be reduced by peroxidases to Generation of Eicosanoids in Zymosan-Induced Peritonitis. Injection 5-hydroxyeicosatetraenoic acid (5-HETE) or dehydrated, in a of zymosan into the peritoneal cavity of mice resulted in second 5LO-catalyzed reaction, to leukotriene A4 (LTA4). 5LO action is facilitated by 5LO-activating protein (FLAP), an inte- gral nuclear membrane protein, and the assembly of a multien- Author contributions: S.Z., M.A.G., R.C.M., and A.S. designed research; S.Z., M.A.G., A.E.R., zymatic machine to make LTs (10–12). Thus, LTA4 is formed and A.S. performed research; S.Z., M.A.G., R.C.M., and A.S. analyzed data; and S.Z., M.A.G., near the nuclear envelope, and this chemically reactive molecule R.C.M., and A.S. wrote the paper. must find its way either to leukotriene C4 synthase (LTC4S), The authors declare no conflict of interest. another nuclear membrane protein that conjugates LTA4 with 1S.Z. and M.A.G. contributed equally to this work. glutathione to form leukotriene C4 (LTC4), or to cytosolic LTA4 2To whom correspondence should be addressed. E-mail: [email protected]. hydrolase (LTA4H), which stereospecifically opens the epoxide 3Present address: Department of Pharmacological Sciences, University of Milan, Via Balza- ring and controls the addition of water at carbon-12 to form retti 9, 20133 Milan, Italy. www.pnas.org͞cgi͞doi͞10.1073͞pnas.0903851106 PNAS Early Edition ͉ 1of6 Downloaded by guest on September 27, 2021 LTE4 5 (m/z 438→333) 6 trans Δ - -LTB4s (m/z 335→195) LTB4 5-HETE 4 m/z ( 335→195) (m/z 319→115) ) LTD4 -3 (m/z 495→177) 3 LTC4 (m/z 624→272) PGE2 2 (m/z 351→271) 5,6-diHETEs (m/z 335→115) TXB2 (m/z 369→169) Intensity (cps x 10 Intensity 1 0 5 10 15 20 25 Time (min) Fig. 1. LC/MS/MS profile of eicosanoids in peritoneal lavage. Mice were treated with 1-mg zymosan for 2 h, and eicosanoids analyzed by LC/MS/MS, monitoring the specific m/z transitions indicated. Retention times of deuterated internal standards (described in the text) coincided with their cognate metabolites. production of eicosanoids, as revealed by liquid chromatogra- with calcium ionophore A23187 (Table 1). In unchallenged mice, phy/tandem mass spectrometry (LC/MS/MS) (Fig. 1). After 2 h, peritoneal cells produced mainly LTC4, consistent with the eicosanoids derived from the 5LO and COX pathways of AA presence of macrophages and mast cells. Upon zymosan treat- oxidation were detected. The most abundant metabolites in ment, there was a time-dependent decrease of cysLT production peritoneal lavage were LTE4, LTB4, and 5-HETE. Also present and an increase in LTB4 production, likely because of macro- 6 were LTC4, LTD4, ⌬ -trans-LTB4 isomers, 5,6-dihydroxyeicosa- phages being replaced by neutrophils. tetraenoic acid (diHETE) isomers, and small amounts of COX- derived thromboxane B2 (TXB2) and prostaglandin E2 (PGE2). Production of Leukotrienes in Transgenic Mice Deficient in Leukotri- Levels of 5,6-diHETEs were consistently higher (2–8 times) than ene Biosynthetic Enzymes. Production of eicosanoids by WT and 6 6 levels of ⌬ -trans-LTB4s. In subsequent experiments, ⌬ -trans- transgenic mice was investigated (Fig. 3). As expected,2hafter Ϫ/Ϫ LTB4s and 5,6-diHETEs are reported together as nonenzymatic zymosan injection the peritoneal lavage of 5LO mice showed products of LTA4. 6-keto-PGF1␣ and PGF2␣ were barely de- no LTB4 and barely detectable amounts of cysLTs. The levels of tected above background (10–20% of the PGE2 signal). PGD2, COX-derived TXB2 and PGE2 were similar to WT mice. No Ϫ/Ϫ PGJ2, PGA2, 20-OH-LTB4, and 20-COOH-LTB4 were below the other COX-derived metabolite was increased in 5LO ani- limit of detection. 12-HETE and 15-HETE were also found, but mals, indicating that no shunting of AA substrate between the 2 their levels were similar in control mice injected with PBS. None oxygenases occurred in this model. These animals showed of the other eicosanoids was detected in mice injected with PBS decreased MPO activity (indicative of neutrophil infiltration) or not treated at all (Fig. 2, 0 h time point). and protein concentration (indicative of plasma extravasation) in Zymosan-induced LT release was time-dependent. LTB4 in- the peritoneal lavage (Table 2), in line with sharply reduced LT Ϫ/Ϫ creased at 1 h and peaked at 2 h (see Fig.
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