LPS and Poly I:C Induce Chromatin Modifications at a Novel Upstream Region of the IL-23 p19 Promoter
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LPS and Poly I:C Induce Chromatin Modifications at a Novel Upstream Region of the IL-23 p19 Promoter Stacey Garrett,1 Michael C. Fitzgerald,1 and Kathleen E. Sullivan1,2
Abstract—IL-23, a heterodimer of IL-12 p40 and IL-23 p19, is critical for an effective immune response to many infections and has been implicated in several autoimmune diseases, however, little is known about the regulation of IL-23 gene expression in monocytes. We found that poly I:C, LPS, flagellin, and zymogen activated significant IL-23 production in primary human monocytes. Using chromatin immunoprecipitation, we found that a distal upstream region of the IL-23 p19 promoter at −601 to −521 underwent extensive histone modifications in response to stimuli. This distal region of the promoter is not highly conserved between species and has not been previously implicated in the regulation of IL-23 expression. Knockdown of CBP markedly decreased IL-23 p19 responses to poly I:C but had a less dramatic effect on LPS responses, confirming different chromatin responses to these two stimuli. Our data suggest that one of the mechanisms regulating IL-23 expression is the regulation of histone modifications at this distal upstream region of the promoter. KEY WORDS: human; monocyte/macrophages; cytokines; histones; chromatin; gene regulation; molecular biology; CBP.
infections. No patients with mutations in either the IL-12 p35 or IL-12Rβ2 have been identified, suggesting that the IL-23 effect is biologically important [3, 13, 46]. In infection models, IL-23 p19 knockout mice have shown that IL-23, and the IL-17 immune response it directs, are critical for the maintenance of the immune response in the face of persistent infections as well as granuloma formation, although anti-fungal responses may be compromised in conditions of high IL-23 [18, 26, 27, 44, 48, 65]. IL-23 acts to facilitate expression of certain cytokines and chemokines and it increases antigen presentation by dendritic cells and microglia [5, 12, 27, 28]. IL-23 is produced primarily by antigen presenting cells, including macrophages and dendritic cells (DCs), in response to a variety of toll-like receptor (TLR) molecules. The IL-23 receptor is expressed on activated/memory T cells, NK cells, and, at a low level, on monocytes, macrophages, and DCs [25]. IL-23 production, in combination with TGFβ and IL-6, directs the development of Th17 T cells [54, 59]. Th17 cells appear to be important in tissue inflammatory responses and these cells have been implicated in some of the effects of IL-23 in both
INTRODUCTION The discovery of IL-23, a heterodimer of the IL-12 p40 chain with the novel IL-23 p19 chain, clarified the conflicting data for the IL-12 p40 and IL-12 p35 knockout mice. IL-12 p35 knockout mice have increased susceptibility to infection, but IL-12 p40 knockout mice are even more susceptible to infections [14, 17, 23, 32, 36]. We now know that the key difference between the two is that IL-12 p40 mice lack both IL-12 and IL-23. The role of IL-23 in the defense against intracellular pathogens in huma
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