Regulation of the IL-21 gene by the NF-κB transcription factor c-Rel.
IL-21 is a member of the common gamma-chain-dependent cytokine family and is a key modulator of lymphocyte development, proliferation, and differentiation. IL-21 is highly expressed in activated CD4(+) T cells and plays a critical role in the expansion and differentiation of the Th cell subsets, Th17 and follicular helper T (T(FH)) cells. Because of its potent activity in both myeloid and lymphoid cell immune responses, it has been implicated in a number of autoimmune diseases and has also been used as a therapeutic agent in the treatment of some cancers. In this study, we demonstrate that c-Rel, a member of the NF-kappaB family of transcription factors, is required for IL-21 gene expression in T lymphocytes. IL-21 mRNA and protein levels are reduced in the CD4(+) cells of rel(-/-) mice when compared with rel(+/+) mice in both in vitro and in vivo models. A c-Rel binding site identified in the proximal promoter of il21 is confirmed to bind c-Rel in vitro and in vivo and to regulate expression from the il21 promoter in T cells. Downstream of IL-21 expression, Th17, T(FH), and germinal center B cell development are also impaired in rel(-/-) mice. The administration of IL-21 protein rescued the development of T(FH) cells but not germinal center B cells. Taken together, c-Rel plays an important role in the expression of IL-21 in T cells and subsequently in IL-21-dependent T(FH) cell development.
Chen
Guobing
G
Gene Expression and Epigenomics Group, Department of Genome Biology, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia.
Hardy
Kristine
K
Bunting
Karen
K
Daley
Stephen
S
Ma
Lina
L
Shannon
M Frances
MF
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D045744:Cell Line, Tumor; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020381:Interleukin-17 / Q000378:metabolism; D007378:Interleukins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism; D000098546:Interleukin-21
D020381:Interleukin-17; D007378:Interleukins; D016328:NF-kappa B; D020569:Proto-Oncogene Proteins c-rel; D000098546:Interleukin-21