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 inflammatory cells into host tissues, which is mediated, in part, by localized production of chemokines. The expression and function of chemokines in vivo appears to be highly selective, though the molecular mechanisms responsible are not well understood. All CXC (IFN-gamma-inducible protein (IP-10), macrophage inflammatory protein (MIP)-2, and KC) and CC (JE/monocyte chemoattractant protein (MCP)-1, MCP-5, MIP-1alpha, MIP-1beta, and RANTES) chemokine genes evaluated were sensitive to stimulation by LPS in vitro and in vivo. While IL-10 suppressed the expression of all LPS-induced chemokine genes evaluated in vitro, treatment with IFN-gamma selectively induced IP-10 and MCP-5 mRNAs, but inhibited LPS-induced MIP-2, KC, JE/MCP-1, MIP-1alpha, and MIP-1beta mRNA and/or protein. Like the response to IFN-gamma, LPS-mediated induction of IP-10 and MCP-5 was Stat1 dependent. Interestingly, only the IFN-gamma-mediated suppression of LPS-induced KC gene expression was IFN regulatory factor-2 dependent. Treatment of mice with LPS in vivo also induced high levels of chemokine mRNA in the liver and lung, with a concomitant increase in circulating protein. Hepatic expression of MIP-1alpha, MIP-1beta, RANTES, and MCP-5 mRNAs were dramatically reduced in Kupffer cell-depleted mice, while IP-10, KC, MIP-2, and MCP-1 were unaffected or enhanced. These findings indicate that selective regulation of chemokine expression in vivo may result from differential response of macrophages to pro- and antiinflammatory stimuli and to cell type-specific patterns of stimulus sensitivity. Moreover, the data suggest that individual chemokine genes are differentially regulated in response to LPS, suggesting unique roles during the sepsis cascade.
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
K M
KM
Kopydlowski
C A
CA
Salkowski
M J
MJ
Cody
N
N
van Rooijen
J
J
Major
T A
TA
Hamilton
S N
SN
Vogel
D000818:Animals; D002478:Cells, Cultured; D018925:Chemokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D019742:Chemokines, CC / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D015536:Down-Regulation / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000502:physiology; D007700:Kinetics; D008070:Lipopolysaccharides / Q000008:administration & dosage* / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018945:Monocyte Chemoattractant Proteins / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis
C491224:Ccl12 protein, mouse; D018925:Chemokines; D019742:Chemokines, CC; D019743:Chemokines, CXC; D008070:Lipopolysaccharides; D018945:Monocyte Chemoattractant Proteins; D012333:RNA, Messenger; D016753:Interleukin-10; D007371:Interferon-gamma