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食事性オメガ3脂肪酸由来代謝物によるアレルギー性皮膚炎抑制メカニズムの解明

雑賀, あずさ 大阪大学 DOI:10.18910/82188

2021.03.24

概要

古くから、食事成分が免疫制御において重要な役割を果たすことが知られている。中でも、エイコサペンタエン酸(EPA)やドコサヘキサエン酸などオメガ3脂肪酸が抗アレルギー・抗炎症効果を持つことが知られていたが、その作用機序については不明な点が多かった。しかしながら、近年、高速液体クロマトグラフィーや質量分析計を用いたリピドミクス解析技術の発展により、抗アレルギー・抗炎症活性を示すオメガ3脂肪酸由来代謝物が同定されてきたことで、その作用機序が明らかになってきた。これら知見の集積と連動し、アレルギーや炎症性疾患に対する新たな創薬シーズとしてオメガ3脂肪酸代謝物が注目されている。

アレルギー性接触皮膚炎は、金属や植物成分、化粧品など様々な製品に含まれる低分子抗原に接触することで引き起こされる疾患である。本疾患に対する一般の治療においてはステロイド剤が用いられるが、皮膚委縮症や毛細血管拡張、感染症などの副作用の懸念や、発症因子の違いによる治療効果の個人差が課題となっており、アレルギー性接触皮膚炎に対する新たな予防、治療法の開発が望まれている。そこで本研究では、新規創薬シーズとしてオメガ3脂肪酸代謝物に着目し、アレルギー性接触皮膚炎に対する効果とその作用機序の解明を行った。

当研究室ではこれまでに、アレルギー性接触皮膚炎の動物実験系である接触過敏症(CHS)モデルを用い、EPAのシトクロムP450(CYP )代謝物である17,18- エポキシエイコサテトラエン酸(17,18-EpETE)が、マウスならびにカニクイザルにおいてアレルギー性接触皮膚炎抑制効果を示すことを明らかにし、その作用機序として、好中球に高発現するGタンパク質共役型受容体であるGPR40を介して好中球の炎症部位への遊走を抑制することを報告していた。本研究では化学合成したラセミ体を用いていたが、異性体間では生理活性が異なる事例が多数存在することから、医薬品素材 とし て の 利 用 を考 え た 際 に は単 一 の 鏡 像 異性 体 を 使 用 する こ と が 推 奨さ れ る 。 そ こで 、 鏡 像 異 性体 で あ る17(S),18(R)-EpETE と17(R),18(S)-EpETE の抗炎症活性を比較する目的で、ラセミ体から各鏡像異性体を単離・精製し、マウスCHS モデルにおける抗炎症活性を評価したところ、17(S),18(R)-EpETE がより強い活性を示すことが明らかになった。これらの結果から、EPAから17(S),18(R)-EpETEを立体選択的に産生するための技術確立が重要であると考えた。一般に酵素によるバイオ変換反応は高い立体選択性を示すことが知られている。そこで、Bacillus megateriumが持つCYPの一種であるBM-3 がEPA を17(S),18(R)-EpETE へと立体選択的に変換することができるという過去の報告に着目し、BM-3酵素を発現する遺伝子組換え大腸菌を作出し、そこにEPAを加えることで17(S),18(R)-EpETEを選択的に作製できる こ と を 確 認 し た 。 さ ら に 、 ラ セ ミ 体 か ら 精 製 し た 17(S),18(R)-EpETE と 同 様 、 本 シ ス テ ム を 用 い て 作 製 し た17(S),18(R)-EpETEもGPR40を介して好中球の仮足形成を抑制し、炎症部位への好中球の浸潤を阻害することでCHSにおける炎症を抑えることを明らかにした。今後、本研究成果を基盤とすることで、微生物酵素を用いた17(S),18(R)-EpETEの立体構造特異的かつ安定した大量生産が可能になると考え、医薬品や機能性食品素材などとしての活用が期待される。

次に、食事として摂取したオメガ3脂肪酸の代謝は体の部位によって異なると仮定し、オメガ3脂肪酸である リノレン酸を多く含有する亜麻仁油を含む餌で飼育したマウスの大腸と皮膚において産生される脂肪酸代謝物の網羅的解析を行った。その結果、大腸では17,18-EpETEが大量に産生されるのに対し、皮膚では12-ヒドロキシエイコサペンタエン酸(12-HEPE)の高産生が認められた。この結果と一致し、腸管では17,18-EpETEの産生に関わるCYP の発現が高いのに対して、皮膚ではEPA から12-HEPEを産生する12- リポキシゲナーゼ(LOX )の発現が高いことが分かった。そこで次に CHS モデルを用いて、皮膚において高産生される 12-HEPE の抗アレルギー・抗炎症効果を評価したところ、 17,18-EpETEと同様、12-HEPEもCHSを抑制することが判明した。17,18-EpETEと同様、12-HEPEで処理したマウスの皮膚においては好中球数の減少が認められたが、好中球に対する直接作用は認められず、17,18-EpETEとは異なる作用機序でCHS を抑制することが示唆された。そこで、好中球以外の細胞を由来とし、好中球の遊走に関わる因子を検討したところ、好中球を誘引するケモカインであるCXCL1とCXCL2の遺伝子発現の抑制が認められた。CXCL1とCXCL2の産生細胞として表皮角化細胞が知られていることから、ヒト表皮角化細胞株HaCaT 細胞を用いた検討を行ったところ、TNFαの刺激により表皮角化細胞において誘導されるCXCL1とCXCL2の遺伝子発現を12-HEPEが抑制すること、その作用は表皮角化細胞に高発現するレチノイド X 受容体 α (RXRα )を介していることが分かった。これらの結果より、12-HEPEは表皮角化細胞に発現するRXRαに作用し、CXCL1とCXCL2の遺伝子発現を抑制することで、好中球の炎症部位への浸潤を阻害し、その結果、CHS の発症抑制に繋がったと考えられた。表皮角化細胞は、アトピー性皮膚炎や乾癬など多様な皮膚疾患の増悪に寄与することから、12-HEPEはアレルギー性接触皮膚炎に限らず炎症が関わる多くの皮膚疾患の抑制にも有効であると予想され、今後の幅広い応用展開が期待される。

本研究により異なる細胞を標的とする2 種類のオメガ3 脂肪酸代謝物を同定したことで、アレルギー性接触皮膚炎に対する薬剤選択の幅を広げる重要な知見を提供した。これら作用点の異なる2 種類のオメガ3 脂肪酸代謝物を併用することで、治療効果を高めることも期待できる。ステロイド剤の場合、過剰な免疫抑制作用が副作用の原因の一つとしてあげられるが、オメガ3脂肪酸代謝物は炎症誘導時に認められる細胞の活性化を抑制することで抗炎症作用を示すことから、安全性が高いと考えられる。今後、17(S),18(R)-EpETE及び12-HEPEのヒトでの応用に向けた検討を進めることで、本研究成果が脂質創薬研究及び皮膚疾患に対する医療発展に貢献すると期待する。

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参考文献

1. Frota KMG, Matias ACG, Arêas JAG. Influence of food components on lipid metabolism: scenarios and perspective on the control and prevention of dyslipidemias. Food Science and Technology. 2010;30:7-14.

2. Lichtenstein AH, Kennedy E, Barrier P, et al. Dietary fat consumption and health. Nutr Rev. 1998;56(5):S3-19.

3. Lee JM, Lee H, Kang S, Park WJ. Fatty acid desaturases, polyunsaturated fatty acid regulation, and biotechnological advances. Nutrients. 2016;8(1):23.

4. Saika A, Nagatake T, Kunisawa J. host- and microbe-dependent dietary lipid metabolism in the control of allergy, inflammation, and immunity. Front Nutr. 2019;6:36.

5. Nagatake T, Kunisawa J. Emerging roles of metabolites of ω3 and ω6 essential fatty acids in the control of intestinal inflammation. Int Immunol. 2019;31(9):569-577.

6. Bindu S, Mazumder S, Bandyopadhyay U. Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective. Biochem Pharmacol. 2020;180:114147.

7. Dyerberg J, Bang HO, Stoffersen E, Moncada S, Vane JR. Eicosapentaenoic acid and prevention of thrombosis and atherosclerosis? Lancet. 1978;2(8081):117-119.

8. Mozaffarian D, Rimm EB. Fish intake, contaminants, and human health: evaluating the risks and the benefits. JAMA. 2006;296(15):1885-1899.

9. Miyata J, Arita M. Role of omega-3 fatty acids and their metabolites in asthma and allergic diseases. Allergol Int. 2015;64(1):27-34.

10. Del Gobbo LC, Imamura F, Aslibekyan S, et al. ω-3 polyunsaturated fatty acid biomarkers and coronary heart disease: Pooling project of 19 cohort studies. JAMA Intern Med. 2016;176(8):1155-1166.

11. Calder PC. Very long-chain n-3 fatty acids and human health: fact, fiction and the future. Proc Nutr Soc. 2018;77(1):52-72. 102

12. Alshatwi AA, Subash-Babu P. Effects of increasing ratios of dietary omega-6/omega-3 fatty acids on human monocyte immunomodulation linked with atherosclerosis. Journal of functional foods. 2018;41:258-267.

13. Wang M, Zhang X, Ma LJ, et al. Omega-3 polyunsaturated fatty acids ameliorate ethanolinduced adipose hyperlipolysis: A mechanism for hepatoprotective effect against alcoholic liver disease. Biochim Biophys Acta Mol Basis Dis. 2017;1863(12):3190-3201.

14. Arita M. Mediator lipidomics in acute inflammation and resolution. J Biochem. 2012;152(4):313-319.

15. Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. Nature. 2014;510(7503):92-101.

16. Serhan CN, Levy BD. Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators. J Clin Invest. 2018;128(7):2657-2669.

17. Serhan CN, Chiang N, Dalli J, Levy BD. Lipid mediators in the resolution of inflammation. Cold Spring Harb Perspect Biol. 2014;7(2):a016311.

18. Ishihara T, Yoshida M, Arita M. Omega-3 fatty acid-derived mediators that control inflammation and tissue homeostasis. Int Immunol. 2019;31(9):559-567.

19. Im DS. Omega-3 fatty acids in anti-inflammation (pro-resolution) and GPCRs. Prog Lipid Res. 2012;51(3):232-237.

20. Schwab JM, Chiang N, Arita M, Serhan CN. Resolvin E1 and protectin D1 activate inflammation-resolution programmes. Nature. 2007;447(7146):869-874.

21. Dona M, Fredman G, Schwab JM, et al. Resolvin E1, an EPA-derived mediator in whole blood, selectively counterregulates leukocytes and platelets. Blood. 2008;112(3):848-855.

22. So JK, Hamstra A, Calame A, Hamann CR, Jacob SE. Another great imitator: allergic contact dermatitis differential diagnosis, clues to diagnosis, histopathology, and treatment. Current Treatment Options in Allergy. 2015;2(4):333-348.

23. Alinaghi F, Bennike NH, Egeberg A, Thyssen JP, Johansen JD. Prevalence of contact allergy in the general population: A systematic review and meta-analysis. Contact 103 Dermatitis. 2019;80(2):77-85.

24. Kabashima K, Honda T, Ginhoux F, Egawa G. The immunological anatomy of the skin. Nat Rev Immunol. 2019;19(1):19-30.

25. Taner S, Ozgen O. Corticosteroids for skin delivery: Challenges and new formulation opportunities. IntechOpen, DOI: 10.5772/53909.

26. Coondoo A, Phiske M, Verma S, Lahiri K. Side-effects of topical steroids: A long overdue revisit. Indian Dermatol Online J. 2014;5(4):416-425.

27. Honda T, Egawa G, Grabbe S, Kabashima K. Update of immune events in the murine contact hypersensitivity model: toward the understanding of allergic contact dermatitis. J Invest Dermatol. 2013;133(2):303-315.

28. Lee HY, Stieger M, Yawalkar N, Kakeda M. Cytokines and chemokines in irritant contact dermatitis. Mediators Inflamm. 2013;2013:916497.

29. Erkes DA, Selvan SR. Hapten-induced contact hypersensitivity, autoimmune reactions, and tumor regression: plausibility of mediating antitumor immunity. J Immunol Res. 2014;2014:175265.

30. Natsuaki Y, Egawa G, Nakamizo S, et al. Perivascular leukocyte clusters are essential for efficient activation of effector T cells in the skin. Nat Immunol. 2014;15(11):1064-1069.

31. Kunisawa J, Arita M, Hayasaka T, et al. Dietary ω3 fatty acid exerts anti-allergic effect through the conversion to 17,18-epoxyeicosatetraenoic acid in the gut. Sci Rep. 2015;5:9750.

32. Nagatake T, Shiogama Y, Inoue A, et al. The 17,18-epoxyeicosatetraenoic acid-G proteincoupled receptor 40 axis ameliorates contact hypersensitivity by inhibiting neutrophil mobility in mice and cynomolgus macaques. J Allergy Clin Immunol. 2018;142(2):470484.e412.

33. Isobe Y, Itagaki M, Ito Y, et al. Comprehensive analysis of the mouse cytochrome P450 family responsible for omega-3 epoxidation of eicosapentaenoic acid. Sci Rep. 2018;8(1):7954. 104

34. Kelly SL, Kelly DE. Microbial cytochromes P450: biodiversity and biotechnology. Where do cytochromes P450 come from, what do they do and what can they do for us? Philos Trans R Soc Lond B Biol Sci. 2013;368(1612):20120476.

35. Capdevila JH, Wei S, Helvig C, et al. The highly stereoselective oxidation of polyunsaturated fatty acids by cytochrome P450BM-3. J Biol Chem. 1996;271(37):2266322671.

36. Shirane N, Sui Z, Peterson JA, Ortiz de Montellano PR. Cytochrome P450BM-3 (CYP102): regiospecificity of oxidation of omega-unsaturated fatty acids and mechanismbased inactivation. Biochemistry. 1993;32(49):13732-13741.

37. Hammerer L, Winkler CK, Kroutil W. Regioselective biocatalytic hydroxylation of fatty acids by cytochrome P450s. Catalysis Letters. 2018;148(3):787-812.

38. Adrio JL, Demain AL. Microbial enzymes: tools for biotechnological processes. Biomolecules. 2014;4(1):117-139.

39. Chapman J, Ismail A, Dinu C. Industrial applications of enzymes: Recent advances, techniques, and outlooks. Catalysts. 2018;8(6):238.

40. Steneberg P, Rubins N, Bartoov-Shifman R, Walker MD, Edlund H. The FFA receptor GPR40 links hyperinsulinemia, hepatic steatosis, and impaired glucose homeostasis in mouse. Cell Metab. 2005;1(4):245-258.

41. Yao FM, Palmer SL, Khanolkar AD, Tian X, Guo J, Makriyannis A. Synthesis of 15N-, 13C-, and 2H-labeled methanandamide analogs. J Label Compd Radiopharm. 2003;46(2):115-129.

42. Misawa N, Nodate M, Otomatsu T, et al. Bioconversion of substituted naphthalenes and βeudesmol with the cytochrome P450 BM3 variant F87V. Appl Microbiol Biotechnol. 2011;90(1):147-157.

43. Saika A, Nagatake T, Kishino S, et al. 17(S), 18(R)‐epoxyeicosatetraenoic acid generated by cytochrome P450 BM-3 from Bacillus megaterium inhibits the development of contact hypersensitivity via G-protein-coupled receptor 40-mediated neutrophil suppression. FASEB BioAdvances. 2020;2(1):59-71. 105

44. Serhan CN, Clish CB, Brannon J, Colgan SP, Chiang N, Gronert K. Novel functional sets of lipid-derived mediators with antiinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing. J Exp Med. 2000;192(8):1197-1204.

45. Endo J, Sano M, Isobe Y, et al. 18-HEPE, an n-3 fatty acid metabolite released by macrophages, prevents pressure overload-induced maladaptive cardiac remodeling. J Exp Med. 2014;211(8):1673-1687.

46. Ishida T, Yoshida M, Arita M, et al. Resolvin E1, an endogenous lipid mediator derived from eicosapentaenoic acid, prevents dextran sulfate sodium-induced colitis. Inflamm Bowel Dis. 2010;16(1):87-95.

47. McConathy J, Owens MJ. Stereochemistry in drug action. Prim Care Companion J Clin Psychiatry. 2003;5(2):70-73.

48. Eriksson T, Björkman S, Höglund P. Clinical pharmacology of thalidomide. Eur J Clin Pharmacol. 2001;57(5):365-376.

49. Vargesson N. Thalidomide-induced teratogenesis: history and mechanisms. Birth Defects Res C Embryo Today. 2015;105(2):140-156.

50. Falck JR, Wallukat G, Puli N, et al. 17(R),18(S)-epoxyeicosatetraenoic acid, a potent eicosapentaenoic acid (EPA) derived regulator of cardiomyocyte contraction: structureactivity relationships and stable analogues. J Med Chem. 2011;54(12):4109-4118.

51. Lauterbach B, Barbosa-Sicard E, Wang MH, et al. Cytochrome P450-dependent eicosapentaenoic acid metabolites are novel BK channel activators. Hypertension. 2002;39(2):609-613.

52. Dézsi CA, Szentes V. The real role of β-blockers in daily cardiovascular therapy. Am J Cardiovasc Drugs. 2017;17(5):361-373.

53. Heit B, Tavener S, Raharjo E, Kubes P. An intracellular signaling hierarchy determines direction of migration in opposing chemotactic gradients. J Cell Biol. 2002;159(1):91-102.

54. Zhang H, Sun C, Glogauer M, Bokoch GM. Human neutrophils coordinate chemotaxis by 106 differential activation of Rac1 and Rac2. J Immunol. 2009;183(4):2718-2728.

55. Wu D. Signaling mechanisms for regulation of chemotaxis. Cell Res. 2005;15(1):52-56.

56. Okamoto F, Saeki K, Sumimoto H, Yamasaki S, Yokomizo T. Leukotriene B4 augments and restores Fc gammaRs-dependent phagocytosis in macrophages. J Biol Chem. 2010;285(52):41113-41121.

57. Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol. 2008;8(5):349-361.

58. Cash JL, Bena S, Headland SE, McArthur S, Brancaleone V, Perretti M. Chemerin15 inhibits neutrophil-mediated vascular inflammation and myocardial ischemia-reperfusion injury through ChemR23. EMBO Rep. 2013;14(11):999-1007.

59. Serhan CN. Resolution phase of inflammation: novel endogenous anti-inflammatory and proresolving lipid mediators and pathways. Annu Rev Immunol. 2007;25:101-137.

60. Weber FC, Németh T, Csepregi JZ, et al. Neutrophils are required for both the sensitization and elicitation phase of contact hypersensitivity. J Exp Med. 2015;212(1):15-22.

61. Mortaz E, Alipoor SD, Adcock IM, Mumby S, Koenderman L. Update on neutrophil function in severe inflammation. Front Immunol. 2018;9:2171.

62. Wang WM, Jin HZ. Role of Neutrophils in Psoriasis. J Immunol Res. 2020;2020:3709749.

63. Bian Z, Guo Y, Ha B, Zen K, Liu Y. Regulation of the inflammatory response: enhancing neutrophil infiltration under chronic inflammatory conditions. J Immunol. 2012;188(2):844-853.

64. Drechsler M, Megens RT, van Zandvoort M, Weber C, Soehnlein O. Hyperlipidemiatriggered neutrophilia promotes early atherosclerosis. Circulation. 2010;122(18):18371845.

65. Choudhary D, Jansson I, Schenkman JB, Sarfarazi M, Stoilov I. Comparative expression profiling of 40 mouse cytochrome P450 genes in embryonic and adult tissues. Arch Biochem Biophys. 2003;414(1):91-100.

66. Choudhary D, Jansson I, Stoilov I, Sarfarazi M, Schenkman JB. Expression patterns of mouse and human CYP orthologs (families 1-4) during development and in different adult tissues. Arch Biochem Biophys. 2005;436(1):50-61.

67. Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013;138(1):103-141.

68. Nebert DW, Wikvall K, Miller WL. Human cytochromes P450 in health and disease. Philos Trans R Soc Lond B Biol Sci. 2013;368(1612):20120431.

69. Martignoni M, Groothuis GM, de Kanter R. Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opin Drug Metab Toxicol. 2006;2(6):875-894.

70. McLaughlin LA, Dickmann LJ, Wolf CR, Henderson CJ. Functional expression and comparative characterization of nine murine cytochromes P450 by fluorescent inhibition screening. Drug Metab Dispos. 2008;36(7):1322-1331.

71. Nelson DR, Zeldin DC, Hoffman SM, Maltais LJ, Wain HM, Nebert DW. Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants. Pharmacogenetics. 2004;14(1):1-18.

72. Nebert DW, Karp CL. Endogenous functions of the aryl hydrocarbon receptor (AHR): intersection of cytochrome P450 1 (CYP1)-metabolized eicosanoids and AHR biology. J Biol Chem. 2008;283(52):36061-36065.

73. Lucas D, Goulitquer S, Marienhagen J, et al. Stereoselective epoxidation of the last double bond of polyunsaturated fatty acids by human cytochromes P450. J Lipid Res. 2010;51(5):1125-1133.

74. Ebisawa A, Hiratsuka M, Sakuyama K, Konno Y, Sasaki T, Mizugaki M. Two novel single nucleotide polymorphisms (SNPs) of the CYP2D6 gene in Japanese individuals. Drug Metab Pharmacokinet. 2005;20(4):294-299.

75. Pietarinen P, Tornio A, Niemi M. High frequency of CYP2D6 ultrarapid metabolizer genotype in the finnish population. Basic Clin Pharmacol Toxicol. 2016;119(3):291-296.

76. Hooper LV. You AhR what you eat: linking diet and immunity. Cell. 2011;147(3):489-491.

77. Jeuken A, Keser BJ, Khan E, Brouwer A, Koeman J, Denison MS. Activation of the Ah receptor by extracts of dietary herbal supplements, vegetables, and fruits. J Agric Food Chem. 2003;51(18):5478-5487.

78. Rakhshandehroo M, Knoch B, Müller M, Kersten S. Peroxisome proliferator-activated receptor alpha target genes. PPAR Res. 2010;2010.

79. Kim YI, Hirai S, Takahashi H, et al. 9-Oxo-10(E),12(E)-Octadecadienoic acid derived from tomato is a potent PPAR α agonist to decrease triglyceride accumulation in mouse primary hepatocytes. Mol Nutr Food Res. 2011;55(4):585-593.

80. Takahashi H, Kamakari K, Goto T, et al. 9-Oxo-10(e),12(z),15(z)-octadecatrienoic acid activates peroxisome proliferator-activated receptor α in hepatocytes. Lipids. 2015;50(11):1083-1091.

81. Rigano D, Sirignano C, Taglialatela-Scafati O. The potential of natural products for targeting PPAR. Acta Pharm Sin B. 2017;7(4):427-438.

82. Sanderson LM, de Groot PJ, Hooiveld GJ, et al. Effect of synthetic dietary triglycerides: a novel research paradigm for nutrigenomics. PLoS One. 2008;3(2):e1681.

83. Kliewer SA, Sundseth SS, Jones SA, et al. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc Natl Acad Sci U S A. 1997;94(9):4318-4323.

84. Xu HE, Lambert MH, Montana VG, et al. Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol Cell. 1999;3(3):397-403.

85. Kishino S, Takeuchi M, Park SB, et al. Polyunsaturated fatty acid saturation by gut lactic acid bacteria affecting host lipid composition. Proc Natl Acad Sci U S A. 2013;110(44):17808-17813.

86. Rouzer CA, Marnett LJ. Cyclooxygenases: structural and functional insights. J Lipid Res. 2009;50 Suppl:S29-34.

87. Marnett LJ, Rowlinson SW, Goodwin DC, Kalgutkar AS, Lanzo CA. Arachidonic acid oxygenation by COX-1 and COX-2. Mechanisms of catalysis and inhibition. J Biol Chem. 1999;274(33):22903-22906.

88. Rowlinson SW, Crews BC, Goodwin DC, Schneider C, Gierse JK, Marnett LJ. Spatial requirements for 15-(R)-hydroxy-5Z,8Z,11Z, 13E-eicosatetraenoic acid synthesis within the cyclooxygenase active site of murine COX-2. Why acetylated COX-1 does not synthesize 15-(R)-hete. J Biol Chem. 2000;275(9):6586-6591.

89. Mashima R, Okuyama T. The role of lipoxygenases in pathophysiology; new insights and future perspectives. Redox Biol. 2015;6:297-310.

90. Tjonahen E, Oh SF, Siegelman J, et al. Resolvin E2: identification and anti-inflammatory actions: pivotal role of human 5-lipoxygenase in resolvin E series biosynthesis. Chem Biol. 2006;13(11):1193-1202.

91. Isobe Y, Arita M, Matsueda S, et al. Identification and structure determination of novel antiinflammatory mediator resolvin E3, 17,18-dihydroxyeicosapentaenoic acid. J Biol Chem. 2012;287(13):10525-10534.

92. Manikandan P, Nagini S. Cytochrome P450 structure, function and clinical significance: A Review. Curr Drug Targets. 2018;19(1):38-54.

93. Panigrahy D, Greene ER, Pozzi A, Wang DW, Zeldin DC. EET signaling in cancer. Cancer Metastasis Rev. 2011;30(3-4):525-540.

94. Roman RJ. P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol Rev. 2002;82(1):131-185.

95. Hirata SI, Nagatake T, Sawane K, et al. Maternal ω3 docosapentaenoic acid inhibits infant allergic dermatitis through TRAIL-expressing plasmacytoid dendritic cells in mice. Allergy. 2020.

96. Boukamp P, Petrussevska RT, Breitkreutz D, Hornung J, Markham A, Fusenig NE. Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line. J Cell Biol. 1988;106(3):761-771.

97. Cattani F, Gallese A, Mosca M, et al. The role of CXCR2 activity in the contact hypersensitivity response in mice. Eur Cytokine Netw. 2006;17(1):42-48.

98. Dilulio NA, Engeman T, Armstrong D, Tannenbaum C, Hamilton TA, Fairchild RL. Groalpha-mediated recruitment of neutrophils is required for elicitation of contact hypersensitivity. Eur J Immunol. 1999;29(11):3485-3495.

99. Takeshita K, Yamasaki T, Nagao K, et al. CRTH2 is a prominent effector in contact hypersensitivity-induced neutrophil inflammation. Int Immunol. 2004;16(7):947-959.

100. Guilloteau K, Paris I, Pedretti N, et al. Skin inflammation induced by the synergistic action of IL-17A, IL-22, Oncostatin M, IL-1alpha, and TNF-alpha recapitulates some features of psoriasis. J Immunol. 2010;184(9):5263-5270.

101. Wahli W, Michalik L. PPARs at the crossroads of lipid signaling and inflammation. Trends Endocrinol Metab. 2012;23(7):351-363.

102. Lengqvist J, Mata De Urquiza A, Bergman AC, et al. Polyunsaturated fatty acids including docosahexaenoic and arachidonic acid bind to the retinoid X receptor alpha ligand-binding domain. Mol Cell Proteomics. 2004;3(7):692-703.

103. Alvarez-Curto E, Milligan G. Metabolism meets immunity: The role of free fatty acid receptors in the immune system. Biochem Pharmacol. 2016;114:3-13.

104. Ecker J, Liebisch G, Patsch W, Schmitz G. The conjugated linoleic acid isomer trans9,trans-11 is a dietary occurring agonist of liver X receptor alpha. Biochem Biophys Res Commun. 2009;388(4):660-666.

105. Bedi S, Hines GV, Lozada-Fernandez VV, et al. Fatty acid binding profile of the liver X receptor α. J Lipid Res. 2017;58(2):393-402.

106. Dawson MI, Xia Z. The retinoid X receptors and their ligands. Biochim Biophys Acta. 2012;1821(1):21-56.

107. Kim HJ, Kim DK, Kim H, et al. Involvement of the BLT2 receptor in the itch-associated scratching induced by 12-(S)-lipoxygenase products in ICR mice. Br J Pharmacol. 2008;154(5):1073-1078.

108. Hammarström S, Lindgren JA, Marcelo C, Duell EA, Anderson TF, Voorhees JJ. Arachidonic acid transformations in normal and psoriatic skin. J Invest Dermatol. 1979;73(2):180-183.

109. Hong SH, Han JE, Ko JS, Do SH, Lee EH, Cho MH. Quantitative determination of 12hydroxyeicosatetraenoic acids by chiral liquid chromatography tandem mass spectrometry in a murine atopic dermatitis model. J Vet Sci. 2015;16(3):307-315.

110. Sorokin AV, Norris PC, English JT, et al. Identification of proresolving and inflammatory lipid mediators in human psoriasis. J Clin Lipidol. 2018;12(4):1047-1060.

111. Pilkington SM, Rhodes LE, Al-Aasswad NM, Massey KA, Nicolaou A. Impact of EPA ingestion on COX- and LOX-mediated eicosanoid synthesis in skin with and without a proinflammatory UVR challenge report of a randomised controlled study in humans. Mol Nutr Food Res. 2014;58(3):580-590.

112. Uhlén M, Fagerberg L, Hallström BM, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015;347(6220):1260419.

113. Human Protein Atlas. https://www.proteinatlas.org/ENSG00000108839-ALOX12. Accessed January 7, 2021

114. Leiria LO, Wang CH, Lynes MD, et al. 12-Lipoxygenase regulates cold adaptation and glucose metabolism by producing the omega-3 lipid 12-HEPE from brown fat. Cell Metab. 2019;30(4):768-783.e767.

115. Johnson EN, Nanney LB, Virmani J, Lawson JA, Funk CD. Basal transepidermal water loss is increased in platelet-type 12-lipoxygenase deficient mice. J Invest Dermatol. 1999;112(6):861-865.

116. Epp N, Fürstenberger G, Müller K, et al. 12R-lipoxygenase deficiency disrupts epidermal barrier function. J Cell Biol. 2007;177(1):173-182.

117. Sawane K, Nagatake T, Hosomi K, et al. Dietary omega-3 fatty acid dampens allergic rhinitis via eosinophilic production of the anti-allergic lipid mediator 15- hydroxyeicosapentaenoic acid in mice. Nutrients. 2019;11(12).

118. Buyanravjikh S, Han S, Lee S, et al. Cryptotanshinone inhibits IgE‑mediated degranulation through inhibition of spleen tyrosine kinase and tyrosine‑protein kinase phosphorylation in mast cells. Mol Med Rep. 2018;18(1):1095-1103.

119. Parravicini V, Gadina M, Kovarova M, et al. Fyn kinase initiates complementary signals required for IgE-dependent mast cell degranulation. Nat Immunol. 2002;3(8):741-748.

120. Galli SJ, Tsai M. IgE and mast cells in allergic disease. Nat Med. 2012;18(5):693-704.

121. Dudeck A, Dudeck J, Scholten J, et al. Mast cells are key promoters of contact allergy that mediate the adjuvant effects of haptens. Immunity. 2011;34(6):973-984.

122. Manabe Y, Yoshimura M, Sakamaki K, et al. 1-Fluoro-2,4-dinitrobenzene and its derivatives act as secretagogues on rodent mast cells. Eur J Immunol. 2017;47(1):60-67.

123. Tiwari P, Nagatake T, Hirata SI, et al. Dietary coconut oil ameliorates skin contact hypersensitivity through mead acid production in mice. Allergy. 2019.

124. Sawada Y, Honda T, Hanakawa S, et al. Resolvin E1 inhibits dendritic cell migration in the skin and attenuates contact hypersensitivity responses. J Exp Med. 2015;212(11):19211930.

125. Ohmori Y, Schreiber RD, Hamilton TA. Synergy between interferon-gamma and tumor necrosis factor-alpha in transcriptional activation is mediated by cooperation between signal transducer and activator of transcription 1 and nuclear factor kappaB. J Biol Chem. 1997;272(23):14899-14907.

126. Kanda N, Shimizu T, Tada Y, Watanabe S. IL-18 enhances IFN-gamma-induced production of CXCL9, CXCL10, and CXCL11 in human keratinocytes. Eur J Immunol. 2007;37(2):338-350.

127. Burke SJ, Lu D, Sparer TE, et al. NF-κB and STAT1 control CXCL1 and CXCL2 gene transcription. Am J Physiol Endocrinol Metab. 2014;306(2):E131-149.

128. Kastner P, Mark M, Leid M, et al. Abnormal spermatogenesis in RXR beta mutant mice. Genes Dev. 1996;10(1):80-92.

129. Huang P, Chandra V, Rastinejad F. Retinoic acid actions through mammalian nuclear receptors. Chem Rev. 2014;114(1):233-254.

130. Gericke J, Ittensohn J, Mihály J, et al. Regulation of retinoid-mediated signaling involved in skin homeostasis by RAR and RXR agonists/antagonists in mouse skin. PLoS One. 2013;8(4):e62643.

131. Li M, Chiba H, Warot X, et al. RXR-alpha ablation in skin keratinocytes results in alopecia and epidermal alterations. Development. 2001;128(5):675-688.

132. Li M, Indra AK, Warot X, et al. Skin abnormalities generated by temporally controlled RXRalpha mutations in mouse epidermis. Nature. 2000;407(6804):633-636.

133. Li M, Messaddeq N, Teletin M, Pasquali JL, Metzger D, Chambon P. Retinoid X receptor ablation in adult mouse keratinocytes generates an atopic dermatitis triggered by thymic stromal lymphopoietin. Proc Natl Acad Sci U S A. 2005;102(41):14795-14800.

134. Goloshchapova K, Stehling S, Heydeck D, Blum M, Kuhn H. Functional characterization of a novel arachidonic acid 12S-lipoxygenase in the halotolerant bacterium Myxococcus fulvus exhibiting complex social living patterns. Microbiologyopen. 2018:e775.

135. Porta H, Rocha-Sosa M. Lipoxygenase in bacteria: a horizontal transfer event? Microbiology (Reading). 2001;147:3199-3200.

136. Saika A, Nagatake T, Hirata S, et al. ω3 fatty acid metabolite, 12-hydroxyeicosapentaenoic acid, alleviates contact hypersensitivity by downregulation of CXCL1 and CXCL2 gene expression in keratinocytes via retinoid X receptor α. FASEB J. 2021 (in press)

137. Tuckermann JP, Kleiman A, Moriggl R, et al. Macrophages and neutrophils are the targets for immune suppression by glucocorticoids in contact allergy. J Clin Invest. 2007;117(5):1381-1390.

138. Resolvyx Pharmaceuticals Inc. Safety and efficacy study of RX-10045 on the signs and symptoms of dry eye. ClinicalTrials.gov Website. https://clinicaltrials.gov/ct2/show/NCT00799552. Accessed November 3, 2020

139. A.T. Resolve SARL. Efficacy and safety of RX-10045 ophthalmic solution for ocular inflammation and pain in cataract surgery. ClinicalTrials.gov Website. https://clinicaltrials.gov/ct2/show/NCT02329743. Accessed November 3, 2020

140. The Forsyth Institute. Safety and preliminary efficacy of lipoxin analog BLXA4-ME oral rinse for the treatment of gingivitis (BLXA4). ClinicalTrials.gov Website. https://clinicaltrials.gov/ct2/show/NCT02342691. Accessed November 3, 2020

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