Egr-2 transcription factor is required for Blimp-1-mediated IL-10 production in IL-27-stimulated CD4+ T cells.
Interleukin-27 (IL-27) suppresses immune responses through inhibition of the development of IL-17 producing Th17 cells and induction of IL-10 production. We previously showed that forced expression of early growth response gene 2 (Egr-2), a transcription factor required for T-cell anergy induction, induces IL-10 and lymphocyte activation gene 3 expression and confers regulatory activity on CD4(+) T cells in vivo. Here, we evaluated the role of Egr-2 in IL-27-induced IL-10 production. Among various IL-10-inducing factors, only IL-27 induced high levels of Egr-2 and lymphocyte activation gene 3 expression. Intriguingly, IL-27 failed to induce IL-10 in Egr-2-deficient T cells. IL-27-mediated induction of Prdm1 that codes B lymphocyte induced maturation protein-1, a transcriptional regulator important for IL-10 production in CD4(+) T cells, was also impaired in the absence of Egr-2. Although IL-27-mediated IL-10 induction was dependent on both STAT1 and STAT3, only STAT3 was required for IL-27-mediated Egr-2 induction. These results suggest that IL-27 signal transduction through Egr-2 and B lymphocyte induced maturation protein-1 plays an important role in IL-10 production. Furthermore, Egr-2-deficient CD4(+) T cells showed dysregulated production of IFN-γ and IL-17 in response to IL-27 stimulation. Therefore, Egr-2 may play key roles in controlling the balance between regulatory and effector cytokines.
Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Yukiko
Y
Iwasaki
Keishi
K
Fujio
Tomohisa
T
Okamura
Atsushi
A
Yanai
Shuji
S
Sumitomo
Hirofumi
H
Shoda
Tomohiko
T
Tamura
Hiroki
H
Yoshida
Patrick
P
Charnay
Kazuhiko
K
Yamamoto
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D051767:Early Growth Response Protein 2 / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis*; D020381:Interleukin-17 / Q000096:biosynthesis / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D000093322:Lymphocyte Activation Gene 3 Protein
D015703:Antigens, CD; D051767:Early Growth Response Protein 2; D020381:Interleukin-17; C513258:Prdm1 protein, mouse; D050796:STAT3 Transcription Factor; D014157:Transcription Factors; D016753:Interleukin-10; D007371:Interferon-gamma; D000074462:Positive Regulatory Domain I-Binding Factor 1; D000093322:Lymphocyte Activation Gene 3 Protein; C000720327:Lag3 protein, mouse