Co-localization of Leukotriene A4Hydrolase with 5-Lipoxygenase in Nuclei of Alveolar Macrophages and Rat Basophilic Leukemia Cells but Not Neutrophils

The synthesis of leukotriene B4 from arachidonic acid requires the sequential action of two enzymes: 5-lipoxygenase and leukotriene A4hydrolase. 5-Lipoxygenase is known to be present in the cytoplasm of some leukocytes and able to accumulate in the nucleoplasm of others. In this study, we asked if leukotriene A4 hydrolase co-localizes with 5-lipoxygenase in different types of leukocytes. Examination of rat basophilic leukemia cells by both immunocytochemistry and immunofluorescence revealed that leukotriene A4 hydrolase, like 5-lipoxygenase, was most abundant in the nucleus, with only minor occurrences in the cytoplasm. The finding of abundant leukotriene A4 hydrolase in the soluble nuclear fraction was substantiated by two different cell fractionation techniques. Leukotriene A4 hydrolase was also found to accumulate together with 5-lipoxygenase in the nucleus of alveolar macrophages. This result was obtained using both in situand ex vivo techniques. In contrast to these results, peripheral blood neutrophils contained both leukotriene A4hydrolase and 5-lipoxygenase exclusively in the cytoplasm. After adherence of neutrophils, 5-lipoxygenase was rapidly imported into the nucleus, whereas leukotriene A4 hydrolase remained cytosolic. Similarly, 5-lipoxygenase was localized in the nucleus of neutrophils recruited into inflamed appendix tissue, whereas leukotriene A4 hydrolase remained cytosolic. These results demonstrate for the first time that leukotriene A4hydrolase can be accumulated in the nucleus, where it co-localizes with 5-lipoxygenase. As with 5-lipoxygenase, the subcellular distribution of leukotriene A4 hydrolase is cell-specific and dynamic, but differences in the mechanisms regulating nuclear import must exist. The degree to which these two enzymes are co-localized may influence their metabolic coupling in the conversion of arachidonic acid to leukotriene B4. The synthesis of leukotriene B4 from arachidonic acid requires the sequential action of two enzymes: 5-lipoxygenase and leukotriene A4hydrolase. 5-Lipoxygenase is known to be present in the cytoplasm of some leukocytes and able to accumulate in the nucleoplasm of others. In this study, we asked if leukotriene A4 hydrolase co-localizes with 5-lipoxygenase in different types of leukocytes. Examination of rat basophilic leukemia cells by both immunocytochemistry and immunofluorescence revealed that leukotriene A4 hydrolase, like 5-lipoxygenase, was most abundant in the nucleus, with only minor occurrences in the cytoplasm. The finding of abundant leukotriene A4 hydrolase in the soluble nuclear fraction was substantiated by two different cell fractionation techniques. Leukotriene A4 hydrolase was also found to accumulate together with 5-lipoxygenase in the nucleus of alveolar macrophages. This result was obtained using both in situand ex vivo techniques. In contrast to these results, peripheral blood neutrophils contained both leukotriene A4hydrolase and 5-lipoxygenase exclusively in the cytoplasm. After adherence of neutrophils, 5-lipoxygenase was rapidly imported into the nucleus, whereas leukotriene A4 hydrolase remained cytosolic. Similarly, 5-lipoxygenase was localized in the nucleus of neutrophils recruited into inflamed appendix tissue, whereas leukotriene A4 hydrolase remained cytosolic. These results demonstrate for the first time that leukotriene A4hydrolase can be accumulated in the nucleus, where it co-localizes with 5-lipoxygenase. As with 5-lipoxygenase, the subcellular distribution of leukotriene A4 hydrolase is cell-specific and dynamic, but differences in the mechanisms regulating nuclear import must exist. The degree to which these two enzymes are co-localized may influence their metabolic coupling in the conversion of arachidonic acid to leukotriene B4. leukotriene 5-lipoxygenase alveolar macrophage diaminobenzidine diamidino-2-phenylindole polymorphonuclear leukocyte rat basophilic leukemia phosphate-buffered saline Leukotriene B4(LTB4)1 is a lipid mediator with important roles in immune defense, inflammation, and disease. For example, LTB4 stimulates chemotaxis (1Ford-Hutchinson A.W. Bray M.A. Doig M.V. Shipley M.E. Smith M.J.H. Nature. 1980; 286: 264-265Crossref PubMed Scopus (1572) Google Scholar), adhesion to endothelium (2Gimbrone M.A.J. Brock A.F. Schafer A.I. J. Clin. Invest. 1984; 74: 1552-1555Crossref PubMed Scopus (152) Google Scholar, 3Tonnesen M. Anderson D. Springer T. Knedler A. Avdi N. Henson P. J. Clin. Invest. 1989; 83: 637-646Crossref PubMed Scopus (181) Google Scholar), degranulation (4Feinmark S.J. Lindgren J.A. Claesson H.E. Malmsten C. Samuelsson B. FEBS Lett. 1981; 136: 141-144Crossref PubMed Scopus (110) Google Scholar, 5Dahlen S.-E. Bjork J. Hedqvist P. Arfors K.-E. Hammarstrom S. Lindgren J.-A. Samuelsson B. Proc. Natl. Acad. Sci. U. S. A. 1981; 78: 3887-3891Crossref PubMed Scopus (788) Google Scholar), superoxide anion generation (6Cunningham F.M. Shipley M.E. Smith M.J. J. Pharm. Pharmacol. 1980; 32: 377-380Crossref PubMed Scopus (46) Google Scholar, 7Claesson H.E. Feinmark S.J. Biochim. Biophys. Acta. 1984; 804: 52-57Crossref PubMed Scopus (30) Google Scholar), and phagocytosis (8Mancuso P. Nana-Sinkam P. Peters-Golden M. Infect. Immun. 2001; 69: 2011-2016Crossref PubMed Scopus (110) Google Scholar) by neutrophils (PMNs). The overproduction of LTB4 plays a role in the pathogenesis of a variety of inflammatory diseases, including glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, acute lung injury, and interstitial lung disease (9Lewis R.A. Austen K.F. Soberman R.J. N. Engl. J. Med. 1990; 323: 645-655Crossref PubMed Scopus (1162) Google Scholar, 10Henderson W.J. Ann. Intern. Med. 1994; 121: 684-697Crossref PubMed Scopus (581) Google Scholar, 11Goetzl E.J. An S. Smith W.L. FASEB J. 1995; 9: 1051-1058Crossref PubMed Scopus (246) Google Scholar). The first step in the synthesis of LTB4 from arachidonic acid is mediated by the enzyme 5-lipoxygenase (5-LO), which catalyzes the insertion of molecular oxygen into arachidonic acid to form 5-hydroperoxyeicosatetraenoic acid as well as its subsequent dehydration to LTA4 (12Samuelsson B. Funk C.D. J. Biol. Chem. 1989; 264: 19469-19472Abstract Full Text PDF PubMed Google Scholar, 13Needleman P. Turk J. Jakschik B.A. Morrison A.R. Lefkowith J.B. Annu. Rev. Biochem. 1986; 55: 69-102Crossref PubMed Google Scholar). LTA4 is then modified by the epoxide hydrolase activity of the enzyme LTA4 hydrolase to generate LTB4 (14Haeggstrom J.Z. Wetterholm A. Medina J.F. Samuelsson B. J. Lipid Mediat. 1993; 6: 1-13PubMed Google Scholar). Independent of its epoxide hydrolase activity, LTA4hydrolase also has an aminopeptidase activity (15Orning L. Gierse J.K. Fitzpatrick F.A. J. Biol. Chem. 1994; 269: 11269-11273Abstract Full Text PDF PubMed Google Scholar, 16Haeggstrom J.Z. Wetterholm A. Vallee B.L. Samuelsson B. Biochem. Biophys. Res. Commun. 1990; 173: 431-437Crossref PubMed Scopus (112) Google Scholar). Several studies demonstrate that 5-LO is present in the cytoplasm of some cell types and in the nucleoplasm of others (17Brock T.G. Paine R.I. Peters-Golden M. J. Biol. Chem. 1994; 269: 22059-22066Abstract Full Text PDF PubMed Google Scholar, 18Chen X.-S. Naumann T.A. Kurre U. Jenkins N.A. Copeland N.G. Funk C.D. J. Biol. Chem. 1995; 270: 17993-17999Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 19Woods J.W. Coffey M.J. Brock T.G. Singer I.I. Peters-Golden M. J. Clin. Invest. 1995; 95: 2035-2040Crossref PubMed Scopus (156) Google Scholar). For example, 5-LO is found in the cytoplasm of peripheral blood neutrophils (17Brock T.G. Paine R.I. Peters-Golden M. J. Biol. Chem. 1994; 269: 22059-22066Abstract Full Text PDF PubMed Google Scholar) but predominantly in the nucleoplasm of alveolar macrophages and rat basophilic leukemia (RBL) cells and mast cells (17Brock T.G. Paine R.I. Peters-Golden M. J. Biol. Chem. 1994; 269: 22059-22066Abstract Full Text PDF PubMed Google Scholar, 18Chen X.-S. Naumann T.A. Kurre U. Jenkins N.A. Copeland N.G. Funk C.D. J. Biol. Chem. 1995; 270: 17993-17999Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 19Woods J.W. Coffey M.J. Brock T.G. Singer I.I. Peters-Golden M. J. Clin. Invest. 1995; 95: 2035-2040Crossref PubMed Scopus (156) Google Scholar). Furthermore, 5-LO can be induced to move into the nucleus after various stimuli. For example, 5-LO moves into the nucleus of PMNs after adherence to surfaces or recruitment from the blood into sites of inflammation (20Brock T.G. McNish R.W. Bailie M.B. Peters-Golden M. J. Biol. Chem. 1997; 272: 8276-8280Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar). Similarly, 5-LO moves into the nucleus of eosinophils after adherence (21Brock T.G. Anderson J.A. Fries F.P. Peters-Golden M. Sporn P.H.S. J. Immunol. 1999; 162: 1669-1676PubMed Google Scholar) or in response to treatment with cytokines (22Cowburn A.S. Holgate S.T. Sampson A.P. J. Immunol. 1999; 163: 456-465PubMed Google Scholar, 23Hsieh F.H. Lam B.K. Penrose J.F. Austen K.F. Boyce J.A. J. Exp. Med. 2001; 193: 123-133Crossref PubMed Scopus (177) Google Scholar). None of the above phenomena are associated with enzyme activation. However, after cell stimulation, 5-LO moves from its site in the cytoplasm or nucleoplasm to become reversibly associated with the nuclear envelope and endoplasmic reticulum (24Rouzer C.A. Kargman S. J. Biol. Chem. 1988; 263: 10980-10988Abstract Full Text PDF PubMed Google Scholar, 25Brock T.G. McNish R.W. Peters-Golden M. Biochem. J. 1998; 329: 519-525Crossref PubMed Scopus (33) Google Scholar). The process of membrane association is calcium-dependent (26Rouzer C.A. Samuelsson B. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 7393-7397Crossref PubMed Scopus (94) Google Scholar) and is thought to be essential for the catalytic action of 5-LO. Our current understanding of the enzyme LTA4 hydrolase holds that it is a soluble protein, presumably located within the cytoplasm. Since 5-LO can accumulate in the nucleus of leukocytes, we hypothesized that LTA4 hydrolase might likewise be found within the nucleoplasm. In this study, we demonstrate that the subcellular distribution of LTA4 hydrolase is cell-specific, co-localizing with 5-LO in the nucleoplasm of resting AMs and RBL cells but in the cytoplasm of resting blood PMNs. However, the regulation of nuclear import of LTA4 hydrolase is distinct from that of 5-LO, since only the latter moves into the nucleus after adherence or recruitment of PMNs. F1 male F-344xBN rats at 6 months of age were obtained from the National Institute on Aging. The rats were housed individually in specific pathogen-free conditions for 2 weeks before experimentation. All procedures were performed in accordance with the Guide for the Care and Use of Laboratory Animals as approved by the Council of the American Physiological Society and the University of Michigan Committee on Use and Care of Animals. Rat basophilic leukemia cells (RBL-1, American Type Culture Collection) were seeded at 1 × 10−5 cell ml−1 in minimal essential medium-α (Life Technologies, Inc.) containing 10% fetal calf serum supplemented with penicillin, streptomycin, and amphotericin B (Life Technologies, Inc.). Cells were fed 2 days after seeding and harvested on the third day for experimentation. In some experiments, RBL cells were pelleted and resuspended in medium without serum at 2 × 105 cells ml−1. An equal volume of medium containing 2 μmA23187 was added to stimulate the cells, and the cells were maintained for 5 min at 37 °C. Primary AMs were obtained by lung lavage of 6-month F-344xBN rats by techniques described previously (27Peters-Golden M. McNish R.W. Hyzy R. Shelly C. Toews G.B. J. Immunol. 1990; 144: 263-270PubMed Google Scholar). Human PMNs were isolated from venous blood obtained from healthy volunteers. Purification involved the sequential steps of centrifugation through Ficoll-Paque (Amersham Pharmacia Biotech), dextran sedimentation, and hypotonic lysis of erythrocytes (20Brock T.G. McNish R.W. Bailie M.B. Peters-Golden M. J. Biol. Chem. 1997; 272: 8276-8280Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar). Viability was assessed by trypan blue exclusion. Cells were >95% neutrophils. For adherence, PMNs were placed on fibronectin-coated glass coverslips in Hanks' balanced salts with calcium and magnesium supplemented with 10 mm HEPES for 30 min at 37 °C. Suspension cultured PMNs were maintained in identical conditions in Teflon tubes. The experimental protocol was approved by the University of Michigan Medical School Institutional Review Board for Approval of Research Involving Human Subjects. Appendix tissues were obtained from anonymous human subjects undergoing surgery for purposes unrelated to this study. Tissues were supplied by the Tissue Procurement Core of the University of Michigan Comprehensive Cancer Center. For immunocytochemistry, RBL cells were diluted to 1 × 105 cells ml−1 with serum-free media, mounted on slides by cytospin, and fixed immediately in −20 °C methanol for 30 min. Mounts were then permeabilized in −20 °C acetone for 3 min and air-dried. For immunohistochemistry, formalin-fixed, paraffin-embedded tissue sections were dewaxed in Americlear and rehydrated through decreasing concentrations of ethanol. All materials were then quenched of endogenous peroxidase activity by treatment with 0.3% hydrogen peroxide for 30 min, washed, and blocked with Powerblock (InnoGenex, San Ramon, CA). Primary antibodies, rabbit polyclonal antibodies raised against human 5-LO and LTA4 hydrolase, were a generous gift from Dr. J. Evans, Merck Frosst Center for Therapeutic Research, were in containing serum LTA4 hydrolase and at °C. After with serum in slides were with for 30 min at 37 then with peroxidase for 30 min at was as peroxidase some were with was performed as described previously T.G. McNish R.W. Peters-Golden M. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar), and after and cells were blocked for 30 min at 37 °C with serum in and with antibodies at 37 °C for 1 Cells were then and with washed, and In some were using diamidino-2-phenylindole were with a and with a using was performed using a with was performed as described (17Brock T.G. Paine R.I. Peters-Golden M. J. Biol. Chem. 1994; 269: 22059-22066Abstract Full Text PDF PubMed Google Scholar). RBL cells × were resuspended in in minimal essential medium-α containing ml−1 B and at 37 °C for 30 min. This was a of and in minimal essential medium-α containing ml−1 B and 1 and at for 30 min at °C. revealed at the and in the at the of the and were harvested from the diluted in an equal volume of minimal essential at × 10 min, and resuspended in mm 5 with mm and An of the was and at × for min at °C to and of and were also for trypan blue and for by immunofluorescence and for with was as described (17Brock T.G. Paine R.I. Peters-Golden M. J. Biol. Chem. 1994; 269: 22059-22066Abstract Full Text PDF PubMed Google Scholar), with cells in with at cells ml−1 and to at for 5 min at °C. cell was by the of trypan blue a of was then at for 10 min at °C to The was then at × for min at °C to and membrane The was resuspended in with with 10 at a with a and at × for min at °C to and In some experiments, 1 mm calcium was in the the fractionation and were performed as described previously M. McNish R. Biochem. Biophys. Res. Commun. 1993; PubMed Scopus Google Scholar). was by a modified and 10 of were by to blocked with with washed, and with was by (Amersham Pharmacia and (Amersham Pharmacia The subcellular distribution of LTA4 hydrolase as well as 5-LO was first in the cell which can generate of LTB4 A.W. J. Pharmacol. PubMed Scopus Google Scholar). immunocytochemistry, for LTA4 hydrolase was in both the cytoplasm and nucleus, with the nucleus the cytoplasm identical results were obtained for was present in the whereas the nucleus Cells in with serum demonstrate was as a to LTA4 hydrolase and 5-LO in it to endogenous peroxidase activity, as may with immunocytochemistry, and it for this the cytoplasm for LTA4hydrolase and 5-LO, whereas the nucleus for both with of both LTA4 hydrolase and 5-LO to the the of and both and distinct for both that the distribution of enzyme was identical to the distribution to that of the 5-LO has to be soluble within the nucleoplasm of resting cells (17Brock T.G. Paine R.I. Peters-Golden M. J. Biol. Chem. 1994; 269: 22059-22066Abstract Full Text PDF PubMed Google Scholar, T.G. McNish R.W. Bailie M.B. Peters-Golden M. J. Biol. Chem. 1997; 272: 8276-8280Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar), it was from the above LTA4 hydrolase was also within the nucleoplasm of RBL cells or associated with the nuclear this RBL cells for LTA4 hydrolase and were by sections for both were LTA4 hydrolase was found to with within the nucleus However, as described the two were that the distribution of LTA4 hydrolase that of the In of 5-LO and distribution in RBL cells, 5-LO was also found to be but identical in distribution to that of the above techniques within if the nuclear is soluble and the molecular as the As to these RBL cells were with and through a this were obtained at the as by for the 3 for and trypan blue as 3 and trypan blue were obtained in the both and contained the 5-LO and the LTA4 hydrolase As previously (17Brock T.G. Paine R.I. Peters-Golden M. J. Biol. Chem. 1994; 269: 22059-22066Abstract Full Text PDF PubMed Google Scholar), from RBL cells 5-LO in both soluble and In LTA4 hydrolase is to the soluble of RBL 3 previously can cells nuclear (17Brock T.G. Paine R.I. Peters-Golden M. J. Biol. Chem. 1994; 269: 22059-22066Abstract Full Text PDF PubMed Google Scholar). this is in the of 5-LO is most abundant in the and it is also in membrane and nuclear T.G. Paine R.I. Peters-Golden M. J. Biol. Chem. 1994; 269: 22059-22066Abstract Full Text PDF PubMed Google and T.G. McNish R.W. Peters-Golden M. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar). this in the LTA4 hydrolase is also predominantly in the and minor can also be in the membrane fraction 5-LO can calcium-dependent membrane association after cell (24Rouzer C.A. Kargman S. J. Biol. Chem. 1988; 263: 10980-10988Abstract Full Text PDF PubMed Google Scholar, S. P. J.F. J. Biol. Chem. Full Text PDF PubMed Google Scholar) and 5-LO and LTA4 hydrolase in it was of to if LTA4hydrolase demonstrate calcium-dependent membrane association or membrane association after cell As cells were in the of the of 5-LO was found to be associated with the membrane and However, in the LTA4 hydrolase remained predominantly with a distribution which that found in cells RBL cells were with 1 μmA23187 for 5 min, that 5-LO to to nuclear whereas in distribution of LTA4 hydrolase was found if nuclear of LTA4hydrolase with 5-LO to leukocytes, we rat which like RBL cells, can abundant M. McNish R.W. Hyzy R. Shelly C. Toews G.B. J. Immunol. 1990; 144: 263-270PubMed Google Scholar). tissue was harvested from and fixed with Tissue were then to the subcellular of LTA4 hydrolase with that of 5-LO in AMs in for LTA4 hydrolase, by the from the peroxidase was in both the cytoplasm and the nucleus of with the nucleus This with the of alveolar cells in which for hydrolase was present in the cytoplasm but from the which were blue to with for 5-LO in AMs within a like that for hydrolase, within the nucleus but also within the cytoplasm. In sections with was The subcellular distribution of LTA4 hydrolase was also assessed in AMs isolated from the lung by LTA4 hydrolase, like 5-LO, was accumulated within the nucleus, for both enzymes was also within the cytoplasm within was by with we that 5-LO is found predominantly in the and of AMs by T.G. McNish R.W. Peters-Golden M. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar). Similarly, LTA4 hydrolase was most abundant in the of rat AMs and in the of LTA4 hydrolase in rat subcellular isolated AMs were to with subsequent fractionation by centrifugation as described were then for LTA4 hydrolase by are membrane nuclear soluble and nuclear In to RBL cells and PMNs abundant However, RBL cells and PMNs from peripheral blood 5-LO in the and the import of 5-LO into the nucleus after adherence of PMNs to surfaces or recruitment of PMNs into sites of inflammation (20Brock T.G. McNish R.W. Bailie M.B. Peters-Golden M. J. Biol. Chem. 1997; 272: 8276-8280Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar). peripheral blood PMNs were maintained in and for LTA4 hydrolase as well as 5-LO by both were found to be exclusively PMNs were to to a fibronectin-coated for 30 min, 5-LO accumulated within the whereas LTA4 hydrolase remained the nucleus The subcellular of LTA4 hydrolase and 5-LO in PMNs were also in using to tissue In PMNs in in healthy rat for 5-LO and LTA4hydrolase was to the cytoplasm. sections of tissue from inflamed appendix were for 5-LO, nuclear of recruited polymorphonuclear cells was as sections from the inflamed tissue for LTA4 hydrolase the associated with polymorphonuclear cells, with associated with tissue and cells and In recruited polymorphonuclear cells as well as tissue cells, hydrolase was predominantly cytosolic. LTA4 hydrolase can with 5-LO in the as in peripheral blood or it can from 5-LO, as it is and 5-LO is in recruited PMNs. In the present study, we techniques to the subcellular distribution of two 5-LO and which to LTB4 from arachidonic for the first time that LTA4 hydrolase can be found in the nucleus, where it co-localizes with 5-LO in resting AMs and RBL In both cell of LTA4 hydrolase and 5-LO were also present in the cytoplasm. also found that LTA4hydrolase co-localizes with 5-LO in the cytoplasm of peripheral blood PMNs. However, in this cell LTA4 hydrolase move into the nucleus with 5-LO after adherence or recruitment of these we 5-LO, LTA4 hydrolase calcium-dependent membrane association or after cell The finding that LTA4 hydrolase can accumulate in the nucleus of AMs and RBL cells is since the current thought is that this enzyme is exclusively the current for this in the its subcellular distribution as with this and cells in 5 and nuclear for LTA4 This that only cell types may nuclear import of LTA4 import of may by whereas nuclear import of like the requires the of a nuclear import which of a of D. U. Annu. Rev. Biol. 1999; PubMed Scopus Google Scholar). LTA4 hydrolase has most at of the of LTA4 hydrolase, by and P. J.Z. Biol. 2001; PubMed Scopus Google Scholar), These are also found on the nuclear the that LTA4 hydrolase with or the nuclear of a nuclear import a step S. Rev. PubMed Scopus Google Scholar) as a for nuclear is that LTA4 hydrolase can be at Feinmark S.J. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar), it is this specific has on subcellular is to the of nuclear import of LTA4 The regulation of the subcellular distribution of LTA4hydrolase can be important in it may LTB4 AMs and RBL cells, which 5-LO with LTA4 hydrolase, LTA4 to as by their to of LTB4 with of In which can 5-LO from LTA4 hydrolase, of LTA4 as well as LTB4 A. M. S. R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). is that of the for the conversion of LTA4 to LTB4 in PMNs in the of 5-LO and LTA4 role for nuclear import of LTA4hydrolase may to regulating the of the Since 5-LO can accumulate in the nucleus, of its be within that LTA4 has a to to of Biochem. Biophys. PubMed Scopus Google Scholar). This in may the to the conversion of LTA4 to the of LTA4 hydrolase with 5-LO in the nucleus might the of LTA4 to to nuclear import of LTA4 hydrolase might be to the aminopeptidase of this that were for LTA4 hydrolase revealed for an aminopeptidase role for the enzyme R.J. J. Immunol. 1999; 163: Google Scholar), it is that a only the enzyme is in a subcellular This In we that LTA4 hydrolase can with 5-LO, within the nucleoplasm of AMs and RBL the import of LTA4 hydrolase into the nucleus with that of 5-LO, as can be in and recruited PMNs. These results that the nuclear import of LTA4 hydrolase is a that only in some cell types specific LTA4 hydrolase is in cell types as and its import in cell types to be Furthermore, to the subcellular distribution of LTA4hydrolase may a role in disease. These be the of

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