Regulation of macrophage chemokine expression by lipopolysaccharide in vitro and in vivo

The host response to Gram-negative LPS is characterized by an influx of inf lammatory cells into host tissues, which is mediated, in part, by localized production of chemokines. The expression and function of chemokines in viv o appears to be highly selective, though the molecular mechanisms responsib le are not well understood.;ill CXC (IFN-gamma-inducible protein (IP-10), m acrophage inflammatory protein (MIP)-2, and KC) and CC (JE/monocyte chemoat tractant protein (MCP)-1, MCP-5, MIP-1 alpha, MIP-1 beta,and RANTES) chemok ine genes evaluated were sensitive to stimulation by LPS in vitro and in vi vo. While IL-lO suppressed the expression of all LPS-induced chemokine gene s evaluated in vitro, treatment with IFN-gamma selectively induced IP-10 an d MCP-5 mRNAs, but inhibited LPS-induced MIP-2, KC, JE/MCP-1, MIP-1 alpha, and MIP-1 beta mRNA and/or protein. Like the response to IFN-gamma, LPS-med iated induction of IP-10 and MCP-5 was Stat1 dependent. Interestingly, only the IFN-gamma-mediated suppression of LPS-induced RC gene expression was I FN regulatory factor-2 dependent. Treatment of mice with LPS in vivo also i nduced high levels of chemokine mRNA in the liver and lung, with a concomit ant increase in circulating protein. Hepatic expression of MIP-1 alpha, MIP -1 beta, RANTES, and MCP-5 mRNAs were dramatically reduced in Kupffer cell- depleted mice, while IP-10, KC, MIP-2, and MCP-I H ere unaffected or enhanc ed. These findings indicate that selective regulation of chemokine expressi on in vivo may result from differential response of macrophages to pro- and antiinflammatory stimuli and to cell type-specific patterns of stimulus se nsitivity, Moreover, the data suggest that individual chemokine genes are d ifferentially regulated in response to LPS, suggesting unique roles during the sepsis cascade.