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Induction of NFATc2 expression by interleukin 6 promotes T helper type 2 differentiation.

Diehl S, Chow CW, Weiss L, Palmetshofer A, Twardzik T, Rounds L, Serfling E, Davis RJ, Anguita J, Rincón M - J. Exp. Med. (2002)

Bottom Line: 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.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 NFATc2 expression and NFAT transcriptional activity represents a novel pathway by which IL-6 can modulate gene expression.

View Article: PubMed Central - PubMed

Affiliation: Immunobiology Program, Department of Medicine, Given Medical Building, University of Vermont, Burlington, VT 05405, USA.

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.

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NFATc2 is required for IL-6–mediated Th2 differentiation. (A) Total RNA from wild-type (WT) or NFATc2-deficient (NFATc2−/−) CD4+ T cells that were stimulated for 2 d in the presence or absence of IL-6 was subjected to RPA analysis. (B) NFATc1 and NFATc3 protein levels were determined by Western blot analysis of whole cell lysates from wild-type and NFATc2−/− CD4+ T cells stimulated for 4 d in the presence or absence of IL-6. Actin is shown as a loading control. (C) CD4+ T cells from wild-type or NFATc2−/− mice were stimulated for 4 d with anti-CD3 and anti-CD28 mAbs in the absence (−) or presence of IL-6. After 4 d cells were washed, restimulated with anti-CD3, and IL-4 production was determined after 24 h. Results are representative of three experiments. (D) NFAT-mediated differentiation of Th2 cells by IL-6.
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fig6: NFATc2 is required for IL-6–mediated Th2 differentiation. (A) Total RNA from wild-type (WT) or NFATc2-deficient (NFATc2−/−) CD4+ T cells that were stimulated for 2 d in the presence or absence of IL-6 was subjected to RPA analysis. (B) NFATc1 and NFATc3 protein levels were determined by Western blot analysis of whole cell lysates from wild-type and NFATc2−/− CD4+ T cells stimulated for 4 d in the presence or absence of IL-6. Actin is shown as a loading control. (C) CD4+ T cells from wild-type or NFATc2−/− mice were stimulated for 4 d with anti-CD3 and anti-CD28 mAbs in the absence (−) or presence of IL-6. After 4 d cells were washed, restimulated with anti-CD3, and IL-4 production was determined after 24 h. Results are representative of three experiments. (D) NFAT-mediated differentiation of Th2 cells by IL-6.

Mentions: To establish whether NFATc2 was indeed required for IL-6 to induce IL-4 expression and Th2 differentiation, we analyzed CD4+ T cells lacking NFATc2 (NFATc2−/−). We first examined whether NFATc2 was required for induction of early IL-4 gene expression by IL-6. CD4+ T cells from wild-type and NFATc2−/− mice were stimulated for 2 d in the absence or presence of IL-6. IL-4 mRNA levels were strongly induced (sixfold) by IL-6 in wild-type CD4+ T cells (Fig. 6 A). However, the presence of IL-6 did not cause a substantial increase in IL-4 mRNA (twofold) in NFATc2−/− CD4+ T cells (Fig. 6 A). Thus, IL-6–induced IL-4 gene expression requires NFATc2. The elevated expression of IL-4 in NFATc2−/− CD4+ T cells compared with wild-type cells stimulated in the absence of IL-6 correlated with previous observations (25, 26). These increased levels of IL-4 in CD4+ T cells lacking NFATc2 might be due to compensation by other NFATc family members. We observed increased levels of NFATc1 and NFATc3 in NFATc2−/− CD4+ T cells (Fig. 6 B). Interestingly, IL-6 did not affect NFATc1 or NFATc3 levels in NFATc2−/− CD4+ T cells, supporting the specific effect of IL-6 on NFATc2.


Induction of NFATc2 expression by interleukin 6 promotes T helper type 2 differentiation.

Diehl S, Chow CW, Weiss L, Palmetshofer A, Twardzik T, Rounds L, Serfling E, Davis RJ, Anguita J, Rincón M - J. Exp. Med. (2002)

NFATc2 is required for IL-6–mediated Th2 differentiation. (A) Total RNA from wild-type (WT) or NFATc2-deficient (NFATc2−/−) CD4+ T cells that were stimulated for 2 d in the presence or absence of IL-6 was subjected to RPA analysis. (B) NFATc1 and NFATc3 protein levels were determined by Western blot analysis of whole cell lysates from wild-type and NFATc2−/− CD4+ T cells stimulated for 4 d in the presence or absence of IL-6. Actin is shown as a loading control. (C) CD4+ T cells from wild-type or NFATc2−/− mice were stimulated for 4 d with anti-CD3 and anti-CD28 mAbs in the absence (−) or presence of IL-6. After 4 d cells were washed, restimulated with anti-CD3, and IL-4 production was determined after 24 h. Results are representative of three experiments. (D) NFAT-mediated differentiation of Th2 cells by IL-6.
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Related In: Results  -  Collection

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fig6: NFATc2 is required for IL-6–mediated Th2 differentiation. (A) Total RNA from wild-type (WT) or NFATc2-deficient (NFATc2−/−) CD4+ T cells that were stimulated for 2 d in the presence or absence of IL-6 was subjected to RPA analysis. (B) NFATc1 and NFATc3 protein levels were determined by Western blot analysis of whole cell lysates from wild-type and NFATc2−/− CD4+ T cells stimulated for 4 d in the presence or absence of IL-6. Actin is shown as a loading control. (C) CD4+ T cells from wild-type or NFATc2−/− mice were stimulated for 4 d with anti-CD3 and anti-CD28 mAbs in the absence (−) or presence of IL-6. After 4 d cells were washed, restimulated with anti-CD3, and IL-4 production was determined after 24 h. Results are representative of three experiments. (D) NFAT-mediated differentiation of Th2 cells by IL-6.
Mentions: To establish whether NFATc2 was indeed required for IL-6 to induce IL-4 expression and Th2 differentiation, we analyzed CD4+ T cells lacking NFATc2 (NFATc2−/−). We first examined whether NFATc2 was required for induction of early IL-4 gene expression by IL-6. CD4+ T cells from wild-type and NFATc2−/− mice were stimulated for 2 d in the absence or presence of IL-6. IL-4 mRNA levels were strongly induced (sixfold) by IL-6 in wild-type CD4+ T cells (Fig. 6 A). However, the presence of IL-6 did not cause a substantial increase in IL-4 mRNA (twofold) in NFATc2−/− CD4+ T cells (Fig. 6 A). Thus, IL-6–induced IL-4 gene expression requires NFATc2. The elevated expression of IL-4 in NFATc2−/− CD4+ T cells compared with wild-type cells stimulated in the absence of IL-6 correlated with previous observations (25, 26). These increased levels of IL-4 in CD4+ T cells lacking NFATc2 might be due to compensation by other NFATc family members. We observed increased levels of NFATc1 and NFATc3 in NFATc2−/− CD4+ T cells (Fig. 6 B). Interestingly, IL-6 did not affect NFATc1 or NFATc3 levels in NFATc2−/− CD4+ T cells, supporting the specific effect of IL-6 on NFATc2.

Bottom Line: 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.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 NFATc2 expression and NFAT transcriptional activity represents a novel pathway by which IL-6 can modulate gene expression.

View Article: PubMed Central - PubMed

Affiliation: Immunobiology Program, Department of Medicine, Given Medical Building, University of Vermont, Burlington, VT 05405, USA.

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.

Show MeSH
Related in: MedlinePlus