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Leukotriene B₄ Potentiates CpG Signaling for Enhanced Cytokine Secretion by Human Leukocytes¹

Laboratory of Innate Immunology, Centre Hospitalier Universitaire de Quebec Research Center (Centre Hospitalier de l’Université Laval) and Department of Molecular Medicine, Laval University, Quebec, Canada

TLRs are known to be important in innate host defense against a variety of microbial infections. In particular, TLR9 has been associated with immune defense against different foreign organisms by recognition of unmethylated DNA sequences. In this report, we provide evidence that leukotriene B₄ (LTB₄) has the capacity to modulate TLR9 expression on human neutrophils. The effect of LTB₄ was found to be specific, because related leukotrienes such as LTC₄ and LTD₄ or neutrophil agonists IL-8 and C5a failed to modulate TLR9 expression in neutrophils. Using fluorochrome-tagged CpG DNA, we observed that LTB₄ treatment also increased TLR9 ligand binding in neutrophils. Moreover, LTB₄ stimulation potentiates CpG-mediated signaling via an endosome-independent mechanism in human neutrophils, leading to enhanced secretion of proinflammatory cytokines. The increase in cytokine secretion by LTB₄ following CpG stimulation of neutrophils was associated with the activation of TGF-β-activated kinase (TAK-1) as well as p38 and c-Jun (JNK) kinases. In contrast, in PBMC LTB₄ leads to an increase in cytokine secretion following CpG stimulation but via a MyD88- and endosome-dependent mechanism. As observed in neutrophils, PBMC stimulation with LTB₄ in the presence of CpG also results in enhanced TAK-1, p38, and JNK phosphorylation/activation. These data provide new evidence underlying the immunomodulatory properties of LTB₄ leading to antimicrobial defense.

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 This project was supported by a grant from The Canadian Institutes of Health Research (to J.G.). E.G. is a recipient of a scholarship from Fondation Dr. Georges Phénix.

J.G. designed the research, E.G. performed the research, and J.G. and E.G. analyzed the data and wrote the manuscript.

² Address correspondence and reprint requests to Dr. Jean Gosselin, Laboratory of Innate Immunology, Centre Hospitalier Universitaire de Québec Research Center Research Center (Centre Hospitalier de l’Université Laval), 2705 Boulevard Laurier, Room T 1–49, Québec, Québec, Canada G1V 4G2. E-mail address: jean.gosselin{at}crchul.ulaval.ca

³ Abbreviations used in this paper: ODN, oligodeoxynucleotide; DA, DNA-dependent activator of IFN regulatory factors; LT, leukotriene; TAK-1, TGF-β-activated kinase-1; TRIF, Toll/IL-1R domain-containing adapter inducing IFN-β; WT, wild type; PBMC, peripheral blood mononuclear cell.