The ability of human neutrophils to express IL-10, a key cytokine whose function is to limit and terminate the inflammatory responses by regulating the expression of pro- and anti-inflammatory mediators, is currently controversial in the literature. In our hands, in fact, stimulation of highly purified populations of human neutrophils with diverse pathogen-associated molecular patterns (PAMPs), including Toll-like receptors (TLR) and C-type lectin receptor (CLR) agonists, or damage-associated molecular patterns (DAMPs), including serum amyloid protein A (SAA), do not trigger any mRNA expression or production of IL-10, differently from autologous monocytes and from studies of other groups. To identify the molecular basis of IL-10 expression in human phagocytes, we evaluated the chromatin modification status at their IL-10 genomic locus. By chromatin immunoprecipitation (ChIP) assays, we analyzed posttranslational modifications of histones associated with genes that are active, repressed or poised for transcriptional activation, including H3K4me3, H4Ac, H3K27Ac and H3K4me1 marks. Differently from autologous IL-10-producing monocytes, none of the marks under evaluation was detected at the IL-10 locus of resting or activated neutrophils. By contrast, elevated H3K4me3, H4Ac, H3K4me1 and H3K27Ac levels were detected at syntenic regions of the IL-10 locus in mouse neutrophils. Altogether, data demonstrate that human neutrophils, differently from either monocytes or mouse neutrophils, cannot switch on the IL-10 gene because its locus is in an inactive state, likely reflecting a neutrophil-specific developmental outcome. Implicitly, data also definitively settle a currently unsolved issue on the capacity of human neutrophils to produce IL-10.
An inactive chromatin configuration at the IL-10 locus in human neutrophils
TAMASSIA, Nicola;Zimmermann, Maili;BAZZONI, Flavia;CASSATELLA, Marco Antonio
2013-01-01
Abstract
The ability of human neutrophils to express IL-10, a key cytokine whose function is to limit and terminate the inflammatory responses by regulating the expression of pro- and anti-inflammatory mediators, is currently controversial in the literature. In our hands, in fact, stimulation of highly purified populations of human neutrophils with diverse pathogen-associated molecular patterns (PAMPs), including Toll-like receptors (TLR) and C-type lectin receptor (CLR) agonists, or damage-associated molecular patterns (DAMPs), including serum amyloid protein A (SAA), do not trigger any mRNA expression or production of IL-10, differently from autologous monocytes and from studies of other groups. To identify the molecular basis of IL-10 expression in human phagocytes, we evaluated the chromatin modification status at their IL-10 genomic locus. By chromatin immunoprecipitation (ChIP) assays, we analyzed posttranslational modifications of histones associated with genes that are active, repressed or poised for transcriptional activation, including H3K4me3, H4Ac, H3K27Ac and H3K4me1 marks. Differently from autologous IL-10-producing monocytes, none of the marks under evaluation was detected at the IL-10 locus of resting or activated neutrophils. By contrast, elevated H3K4me3, H4Ac, H3K4me1 and H3K27Ac levels were detected at syntenic regions of the IL-10 locus in mouse neutrophils. Altogether, data demonstrate that human neutrophils, differently from either monocytes or mouse neutrophils, cannot switch on the IL-10 gene because its locus is in an inactive state, likely reflecting a neutrophil-specific developmental outcome. Implicitly, data also definitively settle a currently unsolved issue on the capacity of human neutrophils to produce IL-10.
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