Tumor Progression Locus 2 (Tpl2) Activates the Mammalian Target of Rapamycin (mTOR) Pathway, Inhibits Forkhead Box P3 (FoxP3) Expression, and Limits Regulatory T Cell (Treg) Immunosuppressive Functions

Li, Xin; Acuff, Nicole; Peeks, Angela; Kirkland, Rebecca A.; Wyatt, Kara D.; Nagy, Tamás; Watford, Wendy T.

doi:10.1074/jbc.m116.718783

Cited by 13 publications

(6 citation statements)

References 65 publications

(77 reference statements)

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“…The immune-regulatory function of Tpl2 is largely attributed to its activation of the MEK/ERK pathway in toll-like receptor (TLR), interleukin-1 receptor (IL-1R), or tumor necrosis factor receptor (TNFR) signaling (34, 35). In addition, Tpl2 also modulate the activation of p38, JNK, protein kinase B, and mammalian target of rapamycin in a context-dependent manner (25, 36). We previously found that Tpl2 functions in astrocytes to mediate IL-17A-induced chemokine ( Cxcl1/2 ) expression through promoting TAK1 phosphorylation and its downstream NF-κB, p38, and JNK activation, whereas ERK activation is not affected (24).…”

Section: Discussionmentioning

confidence: 99%

Tpl2 Protects Against Fulminant Hepatitis Through Mobilization of Myeloid-Derived Suppressor Cells

Pei

Wang

et al. 2019

Front. Immunol.

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Myeloid derived suppressor cells (MDSC) in the liver microenvironment protects against the inflammation-induced liver injury in fulminant hepatitis (FH). However, the molecular mechanism through which MDSC is recruited into the inflamed liver remain elusive. Here we identified a protein kinase Tpl2 as a critical mediator of MDSC recruitment into liver during the pathogenesis of Propionibacterium acnes /LPS-induced FH. Loss of Tpl2 dramatically suppressed MDSC mobilization into liver, leading to exaggerated local inflammation and increased FH-induced mortality. Mechanistically, although the protective effect of Tpl2 for FH-induced mortality was dependent on the presence of MDSC, Tpl2 neither directly targeted myeloid cells nor T cells to regulate FH pathogenesis, but functioned in hepatocytes to mediate the induction of MDSC-attracting chemokine CXCL1 and CXCL2 through modulating IL-25 (also known as IL-17E) signaling. As a consequence, increased MDSC in the inflamed liver specifically restrained the local proliferation of infiltrated pathogenic CD4 + T cells, and thus protected against the inflammation-induced acute liver failure. Together, our findings established Tpl2 as a critical mediator of MDSC recruitment and highlighted the therapeutic potential of Tpl2 for the treatment of FH.

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Section: Discussionmentioning

confidence: 99%

Tpl2 Protects Against Fulminant Hepatitis Through Mobilization of Myeloid-Derived Suppressor Cells

Pei

Wang

et al. 2019

Front. Immunol.

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“…9 T. gondii ESA could diminish the percentage of CD4 + CD25 + Foxp3 + in spleen and inhibit Foxp3 in the maternal-fetal interface. 9 T. gondii ESA could diminish the percentage of CD4 + CD25 + Foxp3 + in spleen and inhibit Foxp3 in the maternal-fetal interface.…”

Section: Introductionmentioning

confidence: 93%

“…Transcription factor forkhead box p3 (Foxp3) mainly modulates the differentiation and functional roles in Tregs . T. gondii ESA could diminish the percentage of CD4 + CD25 + Foxp3 + in spleen and inhibit Foxp3 in the maternal‐fetal interface .…”

Section: Introductionmentioning

confidence: 99%

Excreted‐secreted antigens of Toxoplasma gondii inhibit Foxp3 via IL‐2Rγ/JAK3/Stats pathway

Chen

Huang

Zhu

et al. 2018

J of Cellular Biochemistry

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Toxoplasma gondii excreted-secreted antigens (ESA) could lead to the fetal abortion especially in the early stage of pregnancy. Deficit in regulatory T cells is a critical event in the fetal abortion. Transcription factor forkhead box p3 (Foxp3) mediates differentiation and functional roles on regulatory T cells. Previously, we revealed that ESA inhibited Foxp3 through the suppression of transforming growth factor-β type II receptor, phosphorylation of Smad2, Smad3, and Smad4. Knockdown of Smad2 collaborated with ESA to further inhibit Foxp3. The decrease in Foxp3 caused by ESA reversed via forced expression of Smad2, Smad3, and Smad4, respectively. In this study, we investigate whether other signaling pathways are implicated in ESA-induced Foxp3 downregulation. EL4 cells were cultured and stimulated with ESA. Interleukin-2 receptor γ (IL-2Rγ) chain, Janus kinase 3 (JAK3), signal transducer and activator of transcription 5 (Stat5), Stat3, phosphorylation of Stat5 and Stat3 were assayed by Western blot analysis. Phosphorylation of Stat5 and Stat3 was further measured by cellular immunofluorescence. The expression plasmid of pcDNA3.1-Stat3 and pcDNA3.1-Stat5b was constructed, respectively. The concentration of interleukin-2 (IL-2) in the culture supernatants was detected by enzyme-linked immunosorbent assay. ESA inhibited the level of JAK3, phosphorylation of Stat5 and Stat3, and Foxp3 in EL4 cells. The suppressive effects of ESA on Foxp3 were attenuated by forced expression of Stat5 and Stat3. In addition, ESA suppressed IL-2Rγ in EL4 cells, while IL-2Rγ agonist could markedly reverse the diminished Foxp3 caused by ESA. Furthermore, ESA directly influenced the expression of IL-2Rγ, rather than the availability of IL-2 indirectly. ESA suppressed the level of Foxp3 via inhibiting IL-2Rγ/JAK3/Stats signaling pathway in EL4 cells.

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“…For example, MAP3K8 links IL-17 receptor signaling to TAK1 activation, which leads to increased JNK, p38, and NFκB activity in Th17 cells, promoting autoimmune neuroinflammation [81,82]. Moreover, MAP3K8 activity in T cells limits regulatory T cell (Treg) function by inhibiting FoxP3 expression and lowering production of the immunosuppressive cytokines IL-10 and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) [83]. In addition, TNF-α plays a pivotal role in a variety of autoimmune diseases, causing sustained inflammation and tissue damage [84].…”

Section: Discussionmentioning

confidence: 99%

Hypoxia potentiates monocyte-derived dendritic cells for release of tumor necrosis factor α via MAP3K8

et al. 2018

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Dendritic cells (DCs) constantly sample peripheral tissues for antigens, which are subsequently ingested to derive peptides for presentation to T cells in lymph nodes. To do so, DCs have to traverse many different tissues with varying oxygen tensions. Additionally, DCs are often exposed to low oxygen tensions in tumors, where vascularization is lacking, as well as in inflammatory foci, where oxygen is rapidly consumed by inflammatory cells during the respiratory burst. DCs respond to oxygen levels to tailor immune responses to such low-oxygen environments. In the present study, we identified a mechanism of hypoxia-mediated potentiation of release of tumor necrosis factor α (TNF-α), a pro-inflammatory cytokine with important roles in both anti-cancer immunity and autoimmune disease. We show in human monocyte-derived DCs (moDCs) that this potentiation is controlled exclusively via the p38/mitogen-activated protein kinase (MAPK) pathway. We identified MAPK kinase kinase 8 (MAP3K8) as a target gene of hypoxia-induced factor (HIF), a transcription factor controlled by oxygen tension, upstream of the p38/MAPK pathway. Hypoxia increased expression of MAP3K8 concomitant with the potentiation of TNF-α secretion. This potentiation was no longer observed upon siRNA silencing of MAP3K8 or with a small molecule inhibitor of this kinase, and this also decreased p38/MAPK phosphorylation. However, expression of DC maturation markers CD83, CD86, and HLA-DR were not changed by hypoxia. Since DCs play an important role in controlling T-cell activation and differentiation, our results provide novel insight in understanding T-cell responses in inflammation, cancer, autoimmune disease and other diseases where hypoxia is involved.

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Tumor Progression Locus 2 (Tpl2) Activates the Mammalian Target of Rapamycin (mTOR) Pathway, Inhibits Forkhead Box P3 (FoxP3) Expression, and Limits Regulatory T Cell (Treg) Immunosuppressive Functions

Abstract: The serine/threonine kinase tumor progression locus 2 (Tpl2, also known as Map3k8/Cot) is a potent inflammatory mediator that drives the production of TNF␣, IL-1␤, and IFN␥. We previously demonstrated that Tpl2 regulates T cell receptor (

Cited by 13 publications

References 65 publications

Tpl2 Protects Against Fulminant Hepatitis Through Mobilization of Myeloid-Derived Suppressor Cells

Tpl2 Protects Against Fulminant Hepatitis Through Mobilization of Myeloid-Derived Suppressor Cells

Excreted‐secreted antigens of Toxoplasma gondii inhibit Foxp3 via IL‐2Rγ/JAK3/Stats pathway

Hypoxia potentiates monocyte-derived dendritic cells for release of tumor necrosis factor α via MAP3K8

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