Distinct Roles of Transforming Growth Factor-β-activated Kinase 1 (TAK1)-c-Rel and Interferon Regulatory Factor 4 (IRF4) Pathways in Human T Cell Lymphotropic Virus 1-transformed T helper 17 Cells Producing Interleukin-9

Proteins of the nuclear factor of activated T cells (NFAT) family of transcription factors are critical for lymphocyte activation in the immune system. In particular, NFATs are important regulators of inducible IL-4 gene expression. Interferon regulatory factor 4 (IRF4) is an immune system–restricted interferon regulatory factor that is required for lymphocyte activation, but its molecular functions in the T lineage remain to be elucidated. We demonstrate that IRF4 potently synergizes with NFATc2 to specifically enhance NFATc2-driven transcriptional activation of the IL-4 promoter. This function is dependent on the physical interaction of IRF4 with NFATc2. IRF4 synergizes with NFATc2 and the IL-4–inducing transcription factor, c-maf, to augment IL-4 promoter activity as well as to elicit significant levels of endogenous IL-4 production. Furthermore, naïve T helper cells from mice lacking IRF4 are compromised severely for the production of IL-4 and other Th2 cytokines. The identification of IRF4 as a partner for NFATc2 in IL-4 gene regulation provides an important molecular function for IRF4 in T helper cell differentiation.

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Tumor-Derived Cytokines Dysregulate Macrophage Interferon-γ Responsiveness and Interferon Regulatory Factor-8 Expression

Experimental Biology and Medicine ◽

10.1177/153537020322800305 ◽

2003 ◽

Vol 228 (3) ◽

pp. 270-277 ◽

Cited By ~ 5

Author(s):

David W. Mullins ◽

Ryan S. Martins ◽

Klaus D. Elgert

Keyword(s):

Immune Function ◽

Transforming Growth Factor ◽

Cell Function ◽

Protein A ◽

Transforming Growth Factor Β ◽

Interferon Γ ◽

Interferon Regulatory Factor ◽

Regulatory Factor ◽

Activation Pathways

Tumors can evade immune responses through suppressor signals that dysregulate host effector cell function. In this study we demonstrate that tumor-derived suppressor molecules impede host antitumor immune activity through dysregulation of multiple macrophage (MΦ) pathways, including suppressed production of cytotoxic and immunostimulatory agents and impaired expression of the interferon regulatory factor-8 (IRF-8) protein, a critical transducer of interferon-γ-mediated activation pathways. The tumor-derived immunosuppressive cytokines interieukin-10 and transforming growth factor-β, constrain IRF-8 production by normal MΦs, regardless of priming, and IRF-8 is also dysregulated in primary MΦs from tumorburdened hosts. Collectively, these data describe a new mechanism by which tumors disrupt immune function and suggest that abrogation of tumor-derived immunoregulatory factors in situ can restore immune function and enhance antitumor efficacy.

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Dysregulated T helper cell differentiation in the absence of interferon regulatory factor 4

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.182425099 ◽

2002 ◽

Vol 99 (18) ◽

pp. 11808-11812 ◽

Cited By ~ 178

Author(s):

M. Lohoff ◽

H.-W. Mittrucker ◽

S. Prechtl ◽

S. Bischof ◽

F. Sommer ◽

...

Keyword(s):

Cell Differentiation ◽

Interferon Regulatory Factor ◽

T Helper Cell ◽

Helper Cell ◽

T Helper ◽

Regulatory Factor ◽

Interferon Regulatory Factor 4

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Transcription Factor Smad-Independent T Helper 17 Cell Induction by Transforming-Growth Factor-β Is Mediated by Suppression of Eomesodermin

Immunity ◽

10.1016/j.immuni.2011.02.021 ◽

2011 ◽

Vol 34 (5) ◽

pp. 741-754 ◽

Cited By ~ 89

Author(s):

Kenji Ichiyama ◽

Takashi Sekiya ◽

Naoko Inoue ◽

Taiga Tamiya ◽

Ikko Kashiwagi ◽

...

Keyword(s):

Transcription Factor ◽

Growth Factor ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

T Helper ◽

T Helper 17 ◽

Cell Induction ◽

T Helper 17 Cell

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The role of Th17/Treg-mediated immunoregulation in abortion mice

European Journal of Inflammation ◽

10.1177/2058739218760354 ◽

2018 ◽

Vol 16 ◽

pp. 205873921876035 ◽

Cited By ~ 2

Author(s):

Ning Li ◽

Qinglan Qu ◽

Qian Yan

Keyword(s):

Spontaneous Abortion ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Normal Pregnancy ◽

Treg Cells ◽

Vital Role ◽

Orphan Receptor ◽

T Helper ◽

T Helper 17

In the study, we investigated the immune factors related to T helper 17 (Th17) cells and T regulatory (Treg) cells in spontaneous abortion mice. The expression of Th17 was analyzed by interleukin (IL)-6, IL-17A secretion, RAR-related orphan receptor γt (RORγt) expression, and proportion of CD4+IL-17+ cells. The levels of IL-10, transforming growth factor β (TGF-β), Foxp3, and CD4+Foxp3+ cells were presented the Treg expression. Higher embryo absorption rate was found in spontaneous abortion group than that in normal pregnancy group ( P < 0.01). Compared with the normal pregnancy mice, spontaneous abortion mice showed higher levels of IL-6 and IL-17A and lower levels of IL-10 and TGF-β in serum and in decidua ( P < 0.05). Furthermore, the expressions of Foxp3 and CD4+Foxp3+ cells were significantly decreased in spontaneous abortion mice than those in normal pregnancy mice ( P < 0.05). However, the levels of RORγt and CD4+IL-17+ cells remarkably increased in spontaneous abortion mice ( P < 0.05). The results reveal that Th17/Treg cells may play a vital role in immunoregulation during pregnancy.

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