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12/15-Lipoxygenase Regulates the Inflammatory Response to Bacterial Products In Vivo¹

Vincent Dioszeghy^*, Marcela Rosas^*, Benjamin H. Maskrey^*, Chantal Colmont^*, Nicholas Topley^*, Pavlos Chaitidis, Hartmut Kühn, Simon A. Jones^*, Philip R. Taylor^* and Valerie B. O'Donnell^2,*

^* Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff, United Kingdom; and Institute of Biochemistry, Humboldt University, Berlin, Germany

The peritoneal macrophage (M) is the site of greatest 12/15-lipoxygenase (12/15-LOX) expression in the mouse; however, its immunoregulatory role in this tissue has not been explored. Herein, we show that 12/15-LOX is expressed by 95% of resident peritoneal CD11b^high cells, with the remaining 5% being 12/15-LOX^–. 12/15-LOX⁺ cells are phenotypically defined by high F4/80, SR-A, and Siglec1 expression, and enhanced IL-10 and G-CSF generation. In contrast, 12/15-LOX^– cells are a dendritic cell population. Resident peritoneal M numbers were significantly increased in 12/15-LOX^–/– mice, suggesting alterations in migratory trafficking or cell differentiation in vivo. In vitro, M from 12/15-LOX^–/– mice exhibit multiple abnormalities in the regulation of cytokine/growth factor production both basally and after stimulation with Staphylococcus epidermidis cell-free supernatant. Resident adherent cells from 12/15-LOX^–/– mice generate more IL-1, IL-3, GM-CSF, and IL-17, but less CCL5/RANTES than do cells from wild-type mice, while Staphylococcus epidermidis cell-free supernatant-elicited 12/15-LOX^–/– adherent cells release less IL-12p40, IL-12p70, and RANTES, but more GM-CSF. This indicates a selective effect of 12/15-LOX on peritoneal cell cytokine production. In acute sterile peritonitis, 12/15-LOX⁺ cells and LOX products were cleared, then reappeared during the resolution phase. The peritoneal lavage of 12/15-LOX^–/– mice showed elevated TGF-β1, along with increased immigration of monocytes/M, but decreases in several cytokines including RANTES/CCL5, MCP-1/CCL2, G-CSF, IL-12-p40, IL-17, and TNF-. No changes in neutrophil or lymphocyte numbers were seen. In summary, endogenous 12/15-LOX defines the resident M population and regulates both the recruitment of monocytes/M and cytokine response to bacterial products in vivo.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Funding from the Wellcome Trust was provided to V.B.O., V.D., B.M., C.C., S.A.J., and N.T. Financial support to H.K. was provided by Deutsche Forschungsgemeinschaft (Ku 961/8-2) and by the European Commission (FP6, LSHM-CT-2004-0050333). P.R.T. is an Medical Research Council Senior Fellow (G0601617).

² Address correspondence and reprint requests to Dr. Valerie B. O'Donnell, Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom. E-mail address: o-donnellvb{at}cardiff.ac.uk

³ Abbreviations used in this paper: LOX, lipoxygenase; DC, dendritic cell; HETE, hydroxyeicosatetraenoic acid; LXA₄, lipoxin A₄; MMR, mannose receptor; Mo, monocyte; M, macrophage; SES, Staphylococcus epidermidis cell-free supernatant; WT, wild type.

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