Induction of NFATc2 Expression by Interleukin 6 Promotes T Helper Type 2 Differentiation

Abstract

Interleukin (IL)-6 is produced by professional antigen-presenting cells (APCs) such as B cells, macrophages, and dendritic cells. It has been previously shown that APC-derived IL-6 promotes the differentiation of naive CD4+ T cells into effector T helper type 2 (Th2) cells. Here, we have studied the molecular mechanism for IL-6–mediated Th2 differentiation. During the activation of CD4+ T cells, IL-6 induces the production of IL-4, which promotes the differentiation of these cells into effector Th2 cells. Regulation of IL-4 gene expression by IL-6 is mediated by nuclear factor of activated T cells (NFAT), as inhibition of NFAT prevents IL-6–driven IL-4 production and Th2 differentiation. IL-6 upregulates NFAT transcriptional activity by increasing the levels of NFATc2. The ability of IL-6 to promote Th2 differentiation is impaired in CD4+ T cells that lack NFATc2, demonstrating that NFATc2 is required for regulation of IL-4 gene expression by IL-6. Regulation of NFATc2 expression and NFAT transcriptional activity represents a novel pathway by which IL-6 can modulate gene expression.

Nuclear factor of activated T (NFAT) cells activity within CD4+ T cells is influenced by activation status and tissue localisation

“…For this purpose we employed the use of transgenic mice in which NFAT-driven transcription can be determined by the expression of a luciferase reporter gene. These mice have been used extensively for analysis of NFAT-driven transcriptional activity in different tissues [21,23,35,36]. For detection of luciferase expression, CD4+ T cells obtained from naïve or Flu infected mice were re-stimulated in vitro for 20 h with anti-CD3 mAb.…”

“…The expression of NFATc1 isoforms is regulated during the activation of CD4+ T cells by the usage of different promoters and corresponding polyadenylation signals [18][19][20]. NFATc2 expression is also upregulated during the activation of CD4+ T cells and by IL-6-mediated signals [21].…”

Inhibition of NFAT Specifically in T Cells Prevents Allergic Pulmonary Inflammation

“…Nuclear export of NFAT is facilitated by phosphorylation by kinases such as glycogen synthase kinase 3 (9), c-Jun N-terminal kinase (10,11), p38 mitogen-activated protein kinase (12), and casein kinase II (13). NFATc1 and NFATc2 are also regulated at the level of expression (14,15). NFATc1 is further regulated by alternative splicing and usage of different promoters, resulting in three isoforms with differing functions (16,17).…”

Aspergillus fumigatus Generates an Enhanced Th2-Biased Immune Response in Mice with Defective Cystic Fibrosis Transmembrane Conductance Regulator

“…NFAT is a transcription factor whose activation is heavily dependent on increased intracellular calcium due to its dephosphorylation and nuclear trafficking by the calcium-dependent phosphatase, calcineurin (39). NFAT is involved in the regulation of IL-4 and both NFATc1 and NFATc2 have been shown to bind to the IL-4 locus and promote gene expression (43).…”

“…Binding reactions were performed using 2 g of nuclear proteins and a [ 32 P]dCTP end-labeled double-stranded oligonucleotide probe containing an NFAT binding site from the proximal IL-4 gene promoter (36,37) or a CREB protein site from the somatostatin gene promoter (38,39). Anti-NFATc2 Ab (Upstate Biotechnology) was present during the binding reactions for supershift analysis.…”