| RRC ID |
66840
|
| 著者 |
Sekimata M, Yoshida D, Araki A, Asao H, Iseki K, Murakami-Sekimata A.
|
| タイトル |
Runx1 and RORγt Cooperate to Upregulate IL-22 Expression in Th Cells through Its Distal Enhancer.
|
| ジャーナル |
J Immunol
|
| Abstract |
IL-22 is a cytokine that plays a pivotal role in regulating tissue homeostasis at barrier surfaces and is produced by activated CD4+ Th cells. Currently, the molecular mechanisms regulating Il22 gene expression are still unclear. In this study, we have identified a crucial cis-regulatory element located 32 kb upstream of the mouse Il22 promoter, termed conserved noncoding sequence (CNS)-32. We demonstrated that CNS-32 acts as an enhancer in reporter assays and contains binding motifs for Runt-related transcription factor (Runx)1 and retinoic acid-related orphan receptor γt (RORγt). Mutation of these motifs significantly abrogated the reporter activity, suggesting a role for both factors in the control of enhancer-mediated Il22 expression. Runx1 and RORγt occupancy and elevated histone H4 acetylation at CNS-32 were evident, as naive T cells differentiated into IL-22-producing Th22 cells. Overexpression of Runx1 promoted IL-22 production by inducing RORγt and IL-23 receptor, all critical to Th22 cell induction. Although Runx1 alone enhanced IL-22 production in Th22 cells, it was further enhanced in the presence of RORγt. Conversely, short hairpin RNA-mediated knockdown of core-binding factor β, a cofactor essential for Runx1 activity, was effective in limiting IL-22 production. Collectively, our results suggest that IL-22 production is controlled by a regulatory circuit in which Runx1 induces RORγt and then partners with RORγt to direct Il22 expression through their targeting of the Il22 enhancer.
|
| 巻・号 |
202(11)
|
| ページ |
3198-3210
|
| 公開日 |
2019-6-1
|
| DOI |
10.4049/jimmunol.1800672
|
| PII |
jimmunol.1800672
|
| PMID |
31028121
|
| MeSH |
Amino Acid Motifs / genetics
Animals
Cell Differentiation
Cells, Cultured
Conserved Sequence / genetics
Core Binding Factor Alpha 2 Subunit / genetics
Core Binding Factor Alpha 2 Subunit / metabolism*
Enhancer Elements, Genetic / genetics
Interleukins / genetics
Interleukins / metabolism*
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mutation / genetics
Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism*
Protein Binding
RNA, Small Interfering / genetics
Receptors, Interleukin / genetics
Receptors, Interleukin / metabolism
T-Lymphocytes, Helper-Inducer / immunology*
Up-Regulation
|
| IF |
4.886
|
| リソース情報 |
| 原核生物(大腸菌) |
|
