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Dose-Dependent Differential Regulation of Cytokine Secretion from Macrophages by Fractalkine¹

Noriko Mizutani^*, Toshiharu Sakurai, Takahiro Shibata, Koji Uchida, Jun Fujita, Rei Kawashima^*, Yuki I. Kawamura^*,, Noriko Toyama-Sorimachi^*, Toshio Imai^¶ and Taeko Dohi^2,*,

^* Department of Gastroenterology, Research Institute, International Medical Center of Japan, Tokyo, Japan; Department of Clinical Molecular Biology, Faculty of Medicine, Kyoto University, Kyoto, Japan; Laboratory of Food and Biodynamics, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan; and Core Research for Engineering, Science, and Technology and ^¶ KAN Research Institute Inc., Kobe, Japan

Although expression of the fractalkine (CX3CL1, FKN) is enhanced in inflamed tissues, it is detected at steady state in various organs such as the intestine, and its receptor CX3CR1 is highly expressed in resident-type dendritic cells and macrophages. We hypothesized that FKN might regulate the inflammatory responses of these cells. Therefore, murine macrophages were pretreated with FKN and then stimulated with LPS. We found that macrophages pretreated with 0.03 nM FKN but not with 3 nM FKN secreted 50% less TNF- than did cells treated with LPS alone. Cells treated with 0.03 nM FKN and LPS also showed reduced phosphorylation of ERK1/2 and reduced NF-B p50 subunit. Interestingly, the p65 subunit of NF-B was translocated to the nuclei but redistributed to the cytoplasm in the early phase by forming a complex with peroxisome proliferator-activated receptor (PPAR) . Exogenous 15-deoxy-(12,14)-prostaglandin J2, a natural ligand for PPAR-, also induced redistribution of p65 with decreased TNF- secretion after LPS challenge. Pretreatment with 0.03 nM but not 3 nM FKN increased the cellular levels of 15-deoxy-(12,14)-prostaglandin J2 as well as mRNA of PPAR-. Requirement of PPAR- for the effect of 0.03 nM FKN was confirmed by small interfering RNA of PPAR-. In contrast, pretreatment with 3 nM FKN induced higher levels of IL-23 compared with cells pretreated with 0.03 nM FKN and produced TNF- in a CX3CR1-dependent manner. These dose-dependent differential effects of FKN establish its novel role in immune homeostasis and inflammation.

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 work was supported in part by grants and contracts from the Ministry of Health, Labour and Welfare, the Ministry of Education, Culture, Sports, Science and Technology, the Japan Health Sciences Foundation, Novartis Foundation (Japan) for the Promotion of Science, and the Mitsukoshi Health and Welfare Foundation.

² Address correspondence and reprint requests to Dr. Taeko Dohi, Department of Gastroenterology, Research Institute, International Medical Center of Japan, Toyama 1-21-1, Shinjuku, Tokyo, Japan. E-mail address: dohi{at}ri.imcj.go.jp

³ Abbreviations used in this paper: FKN, fractalkine (CX3CL1); BM, bone marrow-derived macrophage; 15d-PGJ₂, 15-deoxy-^12,14-prostaglandin J2; PPAR-, peroxisome proliferator-activated receptor ; siRNA, small interfering RNA.