Lipid mediator class switching during acute inflammation: signals in resolution

Abstract

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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Acknowledgements

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). https://doi.org/10.1038/89759

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