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* Department of Microbiology and Infectious Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada;
Department of Laboratory Medicine and Pathobiology and Department of Immunology, University of Toronto, Toronto, Ontario, Canada;
Department of Pathology and Rosalind Franklin Comprehensive Diabetes Center, Chicago Medical School, North Chicago, IL 60064; and
Department of Biochemistry, Chosun University School of Medicine, Seosuk-Dong, Gwangju, Korea
Macrophages are activated during an inflammatory response and produce multiple inflammatory cytokines. IL-18 is one of the most important innate cytokines produced from macrophages in the early stages of the inflammatory immune response. Monocyte chemoattractant protein (MCP-1) is expressed in many inflammatory diseases such as multiple sclerosis and rheumatoid arthritis, and its expression is correlated with the severity of the disease. Both IL-18 and MCP-1 have been shown to be involved in inflammatory immune responses. However, it has been unclear whether IL-18 is involved in the induction of MCP-1. This investigation was initiated to determine whether IL-18 can induce MCP-1 production, and if so, by which signal transduction pathways. We found that IL-18 induced the production of MCP-1 in macrophages, which was IL-12-independent and was not mediated by autocrine cytokines such as IFN-
or TNF-
. We then examined signal transduction pathways involved in IL-18-induced MCP-1 production. We found that IL-18 did not activate the I
B kinase/NF-B pathway, evidenced by no degradation of IB and no translocation of NF-B p65 to the nucleus in IL-18-stimulated macrophages. Instead, IL-18 activated the PI3K/Akt and MEK/ERK1/2 pathways. Inhibition of either of these pathways attenuated MCP-1 production in macrophages, and inhibition of both signaling pathways resulted in the complete inhibition of MCP-1 production. On the basis of these observations, we conclude that IL-18 induces MCP-1 production through the PI3K/Akt and MEK/ERK1/2 pathways in macrophages.
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