Synergistic Effect of Interleukin-18 on the Expression of Lipopolysaccharide-Induced IP-10 (CXCL-10) mRNA in Mouse Peritoneal Macrophages

Interleukin (IL)-18, a member of the family of IL-1 cytokine, is one of the principal inducers of interferon-y (IFN-y) in T lymphocytes and natural killer cells. The objective of the present study was to evaluate the effect of IL-18 on the expression of chemokine IP-10 (CXCL-10) mRNA in mouse peritoneal macrophages. IL-18 had very weak direct effect or synergistic effect with IL-12 on the expression of IP-10 mRNA in C57BL/6 mouse peritoneal macrophages. However, IL-18 pretreatment was found to play a cooperative role in the expression of lipopolysaccharide (LPS)-induced IP-10 mRNA. For the expression of LPS-induced IP-10 mRNA, the synergistic effect was detected after 16 h of IL-18 pretreatment prior to LPS stimulation. The expression level of CD14 in cells stimulated with LPS was not changed by IL-18 pretreatment, and the level of IFN-y production during IL-18 pretreatment plus LPS stimulation was barely discernible (0.36±0.31 pg/ml). Namely, the synergistic effect of IL-18 pretreatment was not related to a change of LPS receptor, CD 14 expression, and the production of IFN-y by the interaction between IL-18 and LPS. The synergistic effect of IL-18 pretreatment on the expression of LPS-induced IP-10 was related to not NF-κB but AP-1 activation, and associated with the extracellular signal-regulated kinase (ERK) pathway, one of the mitogen-activated protein kinase signaling pathways. These results provide useful information that may elucidate the mechanisms underlying the effect of IL-18 on the expression of IP-10 mRNA.