STAT-1-mediated repression of monocyte interleukin-10 gene expression in vivo.
There have been substantial advances in understanding the events that regulate gene expression at the cellular and molecular level; however, there has been limited progress integrating this information to understand how biological systems function in vivo. For example, the anti-inflammatory cytokine IL-10 is thought to down-regulate the effects of the pro-inflammatory cytokine IFN-gamma on monocyte activation following LPS stimulation. However, the often-postulated reciprocal regulation of IL-10 gene expression by IFN-gamma has not been studied in vivo. Here we demonstrate that the regulation of IL-10 gene expression has at least two phases following challenge with LPS or a gram-negative organism. In C57BL/6 mice, early IL-10 induction occurs independently of STAT-1, while a delayed active repression of IL-10 gene expression is critically dependent on STAT-1, but only partially dependent upon IFN-alpha/beta and IFN-gamma. This in vivo IL-10 production comes from blood monocytes, but not tissue macrophages, and cannot be reproduced in vitro. This study provides new insights into the regulation of IL-10 following challenge with a gram-negative organism, and highlights the importance of studying these cytokine regulatory pathways in vivo.
Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA.
Jeffrey B
JB
VanDeusen
Manisha H
MH
Shah
Brian
B
Becknell
Bradley W
BW
Blaser
Amy K
AK
Ferketich
Gerard J
GJ
Nuovo
Brian M M
BM
Ahmer
Joan
J
Durbin
Michael A
MA
Caligiuri
D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D016905:Gram-Negative Bacterial Infections / Q000235:genetics / Q000276:immunology; D016898:Interferon-alpha / Q000276:immunology; D016899:Interferon-beta / Q000276:immunology; D007371:Interferon-gamma / Q000172:deficiency / Q000276:immunology*; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*
D016898:Interferon-alpha; D008070:Lipopolysaccharides; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D016753:Interleukin-10; D016899:Interferon-beta; D007371:Interferon-gamma