IL-18 Induces Monocyte Chemotactic Protein-1 Production in Macrophages through the Phosphatidylinositol 3-Kinase/Akt and MEK/ERK1/2 Pathways

Abstract

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-γ or TNF-α. We then examined signal transduction pathways involved in IL-18-induced MCP-1 production. We found that IL-18 did not activate the IκB kinase/NF-κB pathway, evidenced by no degradation of IκBα and no translocation of NF-κB 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.

Interleukin‐18 induces angiogenic factors in rheumatoid arthritis synovial tissue fibroblasts via distinct signaling pathways

“…We found a significant increase of p65 NF B nuclear localization in RA ST fibroblasts stimulated for 30 minutes with IL-18, compared with unstimulated cells (Figure 4C). In contrast to these results, some studies using mouse macrophages and epithelial cells did not demonstrate activation of NF B by IL-18 (40,46), again suggesting that such activation depends on the immune environment and cell type examined.…”

“…Kanakaraj et al and Kalina et al found that IL-18 induces JNK and p38 MAPK activation in natural killer and T helper cell lines (42,43), in accordance with our findings in RA ST fibroblasts. In contrast to those reports, Yoo and colleagues did not observe activation of JNK and p38 MAPK in mouse macrophages (40), reaffirming that IL-18-induced activation of these signaling pathways may depend on cell type.…”

“…The level of MCP-1/CCL2 in RA ST fibroblasts doubled with 24-hour IL-18 treatment. IL-18 induces the activation of signaling mole- cules that are involved in the production of proinflammatory cytokines in RA ST fibroblasts and leukocytes (2,3,25,40). Recently, Yoo et al (40) reported that IL-18 induces MCP-1/CCL2 production by PI3K and ERK-1/2 in mouse peritoneal macrophages.…”

“…IL-18 induces the activation of signaling mole- cules that are involved in the production of proinflammatory cytokines in RA ST fibroblasts and leukocytes (2,3,25,40). Recently, Yoo et al (40) reported that IL-18 induces MCP-1/CCL2 production by PI3K and ERK-1/2 in mouse peritoneal macrophages. In the present study, IL-18-induced production of MCP-1/CCL2 in RA ST fibroblasts was mediated by JNK, PI3K, PKC, and NF B. PKC␣ and JNK-2 antisense ODNs significantly inhibited IL-18-induced production of MCP-1/CCL2 compared with PKC␣ or JNK-2 sense ODNs, while PKC␦ antisense ODN did not.…”

Interleukin-18 binding protein therapy is protective in adriamycin nephropathy

“…IL-18 is also a potent inducer of chemokines [i.e., monocyte chemoattractant protein-1 (MCP-1; CCL2), macrophage inflammatory protein-1␣ (CCL3), and IL-8] which recruit monocytes /macrophages and other leukocytes to sites of injury (56). We have previously demonstrated a pathological role for CCL2 (and CCL5) in adriamycin nephropathy (AN) (50), consistent with studies in other models of inflammatory kidney disease (35,38), and IL-18 has been shown to act as a chemoattractant of human CD4 ϩ T cells (24).…”