Aging-dependent upregulation of IL-23p19 gene expression in dendritic cells is associated with differential transcription factor binding and histone modifications.
Age-associated changes in immune response increase the risk of infection and promote inflammation and autoimmunity in older adults. The newly discovered cytokine IL-23 contributes to the maintenance and expansion of Th-17 cells, which promote proinflammatory responses. Our preliminary findings suggested that Th-17 responses are increased in aged mice. IL-23 consists of p40 and p19 subunits. Expression of the p19 subunit is regulated at the transcriptional level by NF-kappaB p65 and c-Rel transcription factors. Using bone-marrow-derived dendritic cells (DCs) from C57BL/6 mice, we show that IL-23 protein production and p19 subunit mRNA levels are significantly increased in DCs from aged mice after activation with TLR ligands (LPS + R848) when compared with DCs of young adult mice. We found that the increase in p19 expression in aged cells is associated with chromatin remodeling characterized by di- and tri-methylation of histone H3K4 and binding of mainly c-Rel at the p19 promoter. In young DCs, the promoter is tri-methylated only at H3K4 and bound by both p65 and c-Rel. C-Rel knockdown restores p65 binding in aged cells but does not activate p19 expression, suggesting that c-Rel is critical for p19 expression. In addition, p65 knockdown significantly increases c-Rel binding and p19 expression in young DCs to levels close to those detected in old cells. Furthermore, the decrease in p65 binding at the p19 promoter in old DCs was specific to the p19 gene since p65 binding to the IL-12p40 promoter was not significantly different between old and young DCs. Our results demonstrate that selective changes in H3K4 methylation, and c-Rel and p65 binding at the p19 promoter occur in DCs and contribute to the upregulation of the p19 subunit expression and IL-23 protein production observed in aged mice. This suggests epigenetic and transcriptional mechanisms contribute to dysregulated inflammatory and autoimmune responses associated with aging.
El Mezayen
Rabab
R
Section of Infectious Diseases, Department of Internal Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA. relmezay@wfubmc.edu
El Gazzar
Mohamed
M
Myer
Rebecca
R
High
Kevin P
KP
D000375:Aging / Q000276:immunology / Q000502:physiology; D000818:Animals; D016922:Cellular Senescence / Q000276:immunology / Q000502:physiology; D002843:Chromatin / Q000235:genetics / Q000502:physiology; D003713:Dendritic Cells / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism*; D053759:Interleukin-23 / Q000032:analysis / Q000276:immunology / Q000502:physiology; D053760:Interleukin-23 Subunit p19 / Q000235:genetics* / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic / Q000235:genetics; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation
D002843:Chromatin; D006657:Histones; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D020569:Proto-Oncogene Proteins c-rel; D014157:Transcription Factors