Lipid mediator class switching during acute inflammation: signals in resolution


Leukotrienes (LTs) and prostaglandins (PGs) amplify acute inflammation, whereas lipoxins (LXs) have unique anti-inflammatory actions. Temporal analyses of these eicosanoids in clinical and experimental exudates showed early coordinate appearance of LT and PG with polymorphonuclear neutrophil (PMN) recruitment. This was followed by LX biosynthesis, which was concurrent with spontaneous resolution. Human peripheral blood PMNs exposed to PGE2 (as in exudates) switched eicosanoid biosynthesis from predominantly LTB4 and 5-lipoxygenase (5-LO)–initiated pathways to LXA4, a 15-LO product that “stopped” PMN infiltration. These results indicate that first-phase eicosanoids promote a shift to anti-inflammatory lipids: functionally distinct lipid-mediator profiles switch during acute exudate formation to “reprogram” the exudate PMNs to promote resolution.

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Figure 1: LX formation in vivo in human pleural exudates.
Figure 2: Time-course of histological events and eicosanoid generation during acute inflammation and resolution.
Figure 3: PMN traffic and LXA4 in acute inflammation.
Figure 4: PGE2 and forskolin switch the conversion of arachidonate from 5-LO to 15-LO products in human PMNs.
Figure 5: Identification of LXA4 from endogenous sources in human PMN exposed first to PGE2 and then the chemotactic peptide fMLP.
Figure 6: PGE2 and induction of 15-LO in human PMNs.
Figure 7: PGE2-mediated 15-LO expression and RNA processing in human PMNs.

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  1. 1

    Serhan, C. N. in Inflammation: basic principles and clinical correlates (eds. Gallin, J.I. & Snyderman, R.) 373–385 (Lippincott Williams & Wilkins, Philadelphia, 1999).

    Google Scholar 

  2. 2

    Samuelsson, B. in Les Prix Nobel: nobel prizes, presentations, biographies and lectures (ed. The Nobel Foundation) 153–174 (Almqvist & Wiksell, Stockholm, 1982).

    Google Scholar 

  3. 3

    Borgeat, P. & Naccache, P. H. Biosynthesis and biological activity of leukotriene B4 . Clin. Biochem. 23, 459–468 (1990).

    CAS  Article  Google Scholar 

  4. 4

    Godson, C. et al. Cutting edge: lipoxins rapidly stimulate nonphlogistic phagocytosis of apoptotic neutrophils by monocyte-derived macrophages. J. Immunol. 164, 1663–1667 (2000).

    CAS  Article  Google Scholar 

  5. 5

    Bandeira-Melo, C. et al. Cyclooxygenase-2-derived prostaglandin E2 and lipoxin A4 accelerate resolution of allergic edema in Angiostrongylus costaricensis-infected rats: relationship with concurrent eosinophilia. J. Immunol. 164, 1029–1036 (2000).

    CAS  Article  Google Scholar 

  6. 6

    Shen, J. et al. Macrophage-mediated 15-lipoxygenase expression protects against atherosclerosis development. J. Clin. Invest. 98, 2201–2208 (1996).

    CAS  Article  Google Scholar 

  7. 7

    Munger, K. A. et al. Transfection of rat kidney with human 15-lipoxygenase suppresses inflammation and preserves function in experimental glomerulonephritis. Proc. Natl Acad. Sci. USA 96, 13375–13380 (1999).

    CAS  Article  Google Scholar 

  8. 8

    Feinmark, S. J. & Cornicelli, J. A. Is there a role for 15-lipoxygenase in atherogenesis? Biochem. Pharmacol. 54, 953–959 (1997).

    CAS  Article  Google Scholar 

  9. 9

    Narumiya, S., Salmon, J. A., Cottee, F. H., Weatherley, B. C. & Flower, R. J. Arachidonic acid 15-lipoxygenase from rabbit peritoneal polymorphonuclear leukocytes. Partial purification and properties. J. Biol. Chem. 256, 9583–95892 (1981).

    CAS  PubMed  Google Scholar 

  10. 10

    Levy, B. D. et al. Human alveolar macrophages have 15-lipoxygenase and generate 15(S)-hydroxy-5,8,11-cis-13-trans-eicosatetraenoic acid and lipoxins. J. Clin. Invest. 92, 1572–1579 (1993).

    CAS  Article  Google Scholar 

  11. 11

    Kelavkar, U. et al. Human 15-lipoxygenase gene promoter: analysis and identification of DNA binding sites for IL-13-induced regulatory factors in monocytes. Mol. Biol. Rep. 25, 173–182 (1998).

    CAS  Article  Google Scholar 

  12. 12

    Fiore, S. & Serhan, C. N. Formation of lipoxins and leukotrienes during receptor-mediated interactions of human platelets and recombinant human granulocyte/macrophage colony-stimulating factor-primed neutrophils. J. Exp. Med. 172, 1451–1457 (1990).

    CAS  Article  Google Scholar 

  13. 13

    Chavis, C., Vachier, I., Chanez, P., Bousquet, J. & Godard, P. 5(S),15(S)-dihydroxyeicosatetraenoic acid and lipoxin generation in human polymorphonuclear cells: dual specificity of 5-lipoxygenase towards endogenous and exogenous precursors. J. Exp. Med. 183, 1633–1643 (1996).

    CAS  Article  Google Scholar 

  14. 14

    Jenkinson, S. G. & Banschbach, M. W. Radioimmunoassay determinations of prostaglandin E in pleural effusions of varying causes. Am. Rev. Respir. Dis. 126, 21–24 (1982).

    CAS  PubMed  Google Scholar 

  15. 15

    Weissmann, G. Prostaglandins as modulators rather than mediators of inflammation. J. Lipid Mediators 6, 275–286 (1993).

    CAS  Google Scholar 

  16. 16

    Moncada, S., Ferreira, S. H. & Vane, J. R. Prostaglandins, aspirin-like drugs and the oedema of inflammation. Nature 246, 217–219 (1973).

    CAS  Article  Google Scholar 

  17. 17

    Raud, J., Dahlen, S. E., Sydbom, A., Lindbom, L. & Hedqvist, P. Enhancement of acute allergic inflammation by indomethacin is reversed by prostaglandin E2: apparent correlation with in vivo modulation of mediator release. Proc. Natl. Acad. Sci. USA 85, 2315–2319 (1988).

    CAS  Article  Google Scholar 

  18. 18

    Herschman, H. R. Recent progress in the cellular and molecular biology of prostaglandin synthesis. Trends Cardiovasc. Med. 8, 145–150 (1998).

    CAS  Article  Google Scholar 

  19. 19

    Gilroy, D. W. et al. Inducible cyclooxygenase may have anti-inflammatory properties. Nature Med. 5, 698–701 (1999).

    CAS  Article  Google Scholar 

  20. 20

    Light, R. W. Pleural Diseases (Lea & Febiger, Philadelphia, 1990).

    Google Scholar 

  21. 21

    Tessier, P. A. et al. Chemokine networks in vivo: involvement of C-X-C and C-C chemokines in neutrophil extravasation in vivo in response to TNF-α. J. Immunol. 159, 3595–3602 (1997).

    CAS  PubMed  Google Scholar 

  22. 22

    Clish, C. B. et al. Local and systemic delivery of a stable aspirin-triggered lipoxin prevents neutrophil recruitment in vivo. Proc. Natl. Acad. Sci. USA 96, 8247–8252 (1999).

    CAS  Article  Google Scholar 

  23. 23

    Chiang, N. et al. Leukotriene B4 receptor transgenic mice reveal novel protective roles for lipoxins and aspirin-triggered lipoxins in reperfusion. J. Clin. Invest. 104, 309–316 (1999).

    CAS  Article  Google Scholar 

  24. 24

    Mayadas, T. N. et al. Acute passive anti-glomerular basement membrane nephritis in P-selectin-deficient mice. Kidney Int. 49, 1342–1349 (1996).

    CAS  Article  Google Scholar 

  25. 25

    Xiao, G. et al. Analysis of hydroperoxide-induced tyrosyl radicals and lipoxygenase activity in aspirin-treated human prostaglandin H synthase-2. Biochemistry 36, 1836–1845 (1997).

    CAS  Article  Google Scholar 

  26. 26

    Izumi, T., Radmark, O., Jornvall, H. & Samuelsson, B. Purification of two forms of arachidonate 15-lipoxygenase from human leukocytes. Eur. J. Biochem. 202, 1231–1238 (1991).

    CAS  Article  Google Scholar 

  27. 27

    Pouliot, M. et al. Expression and activity of prostaglandin endoperoxide synthase-2 in agonist-activated human neutrophils. FASEB J. 12, 1109–1123 (1998).

    CAS  Article  Google Scholar 

  28. 28

    Borrelli, E., Montmayeur, J. P., Foulkes, N. S. & Sassone-Corsi, P. Signal transduction and gene control: the cAMP pathway. Crit. Rev. Oncogenesis 3, 321–338 (1992).

    CAS  PubMed  Google Scholar 

  29. 29

    Clish, C. B., Levy, B. D., Chiang, N., Tai, H. H. & Serhan, C. N. Oxidoreductases in lipoxin A4 metabolic inactivation: a novel role for 15-oxoprostaglandin 13-reductase/leukotriene B4 12-hydroxydehydrogenase in inflammation. J. Biol. Chem. 275, 25372–25380 (2000).

    CAS  Article  Google Scholar 

  30. 30

    Kapff, C. T. & Jandl, J. H. Blood: atlas and sourcebook of hematology (Little, Brown and Co., Boston, MA, 1991).

    Google Scholar 

  31. 31

    Beaulieu, A. D., Paquin, R., Rathanaswami, P. & McColl, S. R. Nuclear signaling in human neutrophils. Stimulation of RNA synthesis is a response to a limited number of proinflammatory agonists. J. Biol. Chem. 267, 426–432 (1992).

    CAS  PubMed  Google Scholar 

  32. 32

    Thiele, B. J. et al. Tissue-specific translational regulation of alternative rabbit 15-lipoxygenase mRNAs differing in their 3′-untranslated regions. Nucleic Acids Res. 27, 1828–1836 (1999).

    CAS  Article  Google Scholar 

  33. 33

    Kritzik, M. R., Ziober, A. F., Dicharry, S., Conrad, D. J. & Sigal, E. Characterization and sequence of an additional 15-lipoxygenase transcript and of the human gene. Biochim. Biophys. Acta 1352, 267–281 (1997).

    CAS  Article  Google Scholar 

  34. 34

    Pouliot, M., Clish, C. B., Petasis, N. A., Van Dyke, T. E. & Serhan, C. N. Lipoxin A(4) analogues inhibit leukocyte recruitment to Porphyromonas gingivalis: a role for cyclooxygenase-2 and lipoxins in periodontal disease. Biochemistry 39, 4761–4768 (2000).

    CAS  Article  Google Scholar 

  35. 35

    Sato, T., Kirimura, Y. & Mori, Y. The co-culture of dermal fibroblasts with human epidermal keratinocytes induces increased prostaglandin E2 production and cyclooxygenase 2 activity in fibroblasts. J. Invest. Dermatol. 109, 334–339 (1997).

    CAS  Article  Google Scholar 

  36. 36

    Shinmura, K. et al. Cyclooxygenase-2 mediates the cardioprotective effects of the late phase of ischemic preconditioning in conscious rabbits. Proc. Natl Acad. Sci. USA 97, 10197–10202 (2000).

    CAS  Article  Google Scholar 

  37. 37

    Swan, S. K. et al. Effect of cyclooxygenase-2 inhibition on renal function in elderly persons receiving a low-salt diet. Ann. Internal Med. 133, 1–9 (2000).

    CAS  Article  Google Scholar 

  38. 38

    Clish, C. B. et al. Local and systemic delivery of a stable aspirin-triggered lipoxin prevents neutrophil recruitment in vivo. Proc. Natl Acad Sci USA 96, 8247–8252 (1999).

    CAS  Article  Google Scholar 

  39. 39

    Serhan, C. N. et al. Design of lipoxin A4 stable analogs that block transmigration and adhesion of human neutrophils. Biochemistry 34, 14609–14615 (1995).

    CAS  Article  Google Scholar 

  40. 40

    Krump, E., Picard, S., Mancini, J. & Borgeat, P. Suppression of leukotriene B4 biosynthesis by endogenous adenosine in ligand-activated human neutrophils. J. Exp. Med. 186, 1401–1406 (1997).

    CAS  Article  Google Scholar 

  41. 41

    McDonald, P. P., Bald, A. & Cassatella, M. A. Activation of the NF-κB pathway by inflammatory stimuli in human neutrophils. Blood 89, 3421–3433 (1997).

    CAS  PubMed  Google Scholar 

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We thank S. Colgan and M. Pouliot for helpful discussions on EMSA and northern blotting, respectively; E. Kim and J. Brannon for technical assistance; and M. H. Small for preparing the manuscript. Supported, in part, by National Institutes of Health grants NHLBI-K08-HL03788 (to B. D. L.), F32-AI10389 (to K. G.) and GM-38765, DK50305 and PO1-DE13499 (to C. N. S.).

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Correspondence to Charles N. Serhan.

Supplementary information

Web Figure 1.

Anti-PMN antisera reduces both exudate PMN numbers and LXA4 . Murine air pouch exudates were collected 8 h after injection of TNF-α (10 ng). To reduce circulating PMNs, mice were given anti-murine PMN antisera (0.3 ml of 1:10 dilution, i.p., 24 h before TNF-α and 0.1 ml of 1:100 dilution, i.v., 1 h before TNF-α). PMNs were enumerated and LXA4 levels determined by ELISA. Values represent the mean for n=3. (GIF 15 kb)

Web Figure 2.

EMSA for 15-LO CRE in PMN nuclear lysates: PGE2 concentration response. Represent–ative EMSA for 15-LO CRE using nuclear lysates from PMNs exposed to PGE2 (0-300 nM, 60 min, 37 °C, see Methods). Values represent the incremental increase above that seen with cells incubated in the absence of PGE2 (as determined by densitometry). (GIF 12 kb)

Web Figure 3.

Human PMN and eosinophil 15-lipoxygenase sequence comparison. (GIF 39 kb)

Web Figure 4.

PGE2 stimulates interactions between phosphorylated CREB-1 and 15-LO. PMNs were incubated (50 x 106 cells/ml, 0–60 min, 37° C) with PGE2 (300 nM). Representative time-course for the gel-shift observed for 15-LO CRE and PMN nuclear extracts (Nuc. Extr.). To determine specific interaction between the putative 15-LO CRE and PMN Nuc. Extr. 125-fold excess unlabled oligo or selective antibodies for CREB-1 (c1), CREB-2 (c2) and phosphorylatd CREB-1 (PO4) were used. (JPG 36 kb)

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Levy, B., Clish, C., Schmidt, B. et al. Lipid mediator class switching during acute inflammation: signals in resolution. Nat Immunol 2, 612–619 (2001).

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