Dose-Dependent Differential Regulation of Cytokine Secretion from Macrophages by Fractalkine
Autor: | Taeko Dohi, Rei Kawashima, Noriko Mizutani, Koji Uchida, Toshiharu Sakurai, Takahiro Shibata, Toshio Imai, Yuki I. Kawamura, Noriko Toyama-Sorimachi, Jun Fujita |
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Rok vydání: | 2007 |
Předmět: |
Lipopolysaccharides
Male Small interfering RNA Immunology Inflammation Biology Ligands Mice CX3CR1 medicine Animals Immunology and Allergy Secretion RNA Messenger Phosphorylation Receptor CX3CL1 Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Dose-Response Relationship Drug Chemokine CX3CL1 Prostaglandin D2 Reverse Transcriptase Polymerase Chain Reaction Tumor Necrosis Factor-alpha Macrophages NF-kappa B Cell biology Mice Inbred C57BL PPAR gamma Cytokine secretion Tumor necrosis factor alpha medicine.symptom |
Zdroj: | The Journal of Immunology. 179:7478-7487 |
ISSN: | 1550-6606 0022-1767 |
Popis: | 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-α 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-κB p50 subunit. Interestingly, the p65 subunit of NF-κB was translocated to the nuclei but redistributed to the cytoplasm in the early phase by forming a complex with peroxisome proliferator-activated receptor (PPAR) γ. Exogenous 15-deoxy-Δ(12,14)-prostaglandin J2, a natural ligand for PPAR-γ, also induced redistribution of p65 with decreased TNF-α secretion after LPS challenge. Pretreatment with 0.03 nM but not 3 nM FKN increased the cellular levels of 15-deoxy-Δ(12,14)-prostaglandin J2 as well as mRNA of PPAR-γ. Requirement of PPAR-γ for the effect of 0.03 nM FKN was confirmed by small interfering RNA of PPAR-γ. 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-α in a CX3CR1-dependent manner. These dose-dependent differential effects of FKN establish its novel role in immune homeostasis and inflammation. |
Databáze: | OpenAIRE |
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