Involvement of PU.1 in the transcriptional regulation of TNF-α

Fukai, Tatsuo; Nishiyama, Chiharu; Kanada, Shunsuke; Nakano, Nobuhiro; Hara, Mutsuko; Tokura, Tomoko; Ikeda, Shigaku; Ogawa, Hideoki; Okumura, Ko

doi:10.1016/j.bbrc.2009.07.126

Cited by 23 publications

(14 citation statements)

References 27 publications

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“…It is reported that PU.1 binds to the promoter and regulates the transcription of TNF␣, IL-1␤, and IL-6 in bone marrow-derived dendritic cells and mast cells (8,49,59). We found that PU.1 also regulated the transcription of these proinflammatory cytokines in adipocytes since silencing PU.1 represses the expression of these proinflammatory factors (Fig.…”

Section: Discussionmentioning

confidence: 55%

Adipocyte expression of PU.1 transcription factor causes insulin resistance through upregulation of inflammatory cytokine gene expression and ROS production

Lin

Pang

Chen

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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We have reported previously that ETS family transcription factor PU.1 is expressed in mature adipocytes of white adipose tissue. PU.1 expression is increased greatly in mouse models of genetic or diet-induced obesity. Here, we show that PU.1 expression is increased only in visceral but not subcutaneous adipose tissues of obese mice, and the adipocytes are responsible for this increase in PU.1 expression. To further address PU.1's physiological function in mature adipocytes, PU.1 was knocked down in 3T3-L1 cells using retroviral-mediated expression of PU.1-targeting shRNA. Consistent with previous findings that PU.1 regulates its target genes, such as NADPH oxidase subunits and proinflammatory cytokines in myeloid cells, the mRNA levels of proinflammatory cytokines (TNFα, IL-1β, and IL-6) and cytosolic components of NADPH oxidase (p47phox and p40phox) were downregulated significantly in PU.1-silenced adipocytes. NADPH oxidase is a main source for reactive oxygen species (ROS) generation. Indeed, silencing PU.1 suppressed NADPH oxidase activity and attenuated ROS in basal or hydrogen peroxide-treated adipocytes. Silencing PU.1 in adipocytes suppressed JNK1 activation and IRS-1 phosphorylation at Ser307. Consequently, PU.1 knockdown improved insulin signaling and increased glucose uptake in basal and insulin-stimulated conditions. Furthermore, knocking down PU.1 suppressed basal lipolysis but activated stimulated lipolysis. Collectively, these findings indicate that obesity induces PU.1 expression in adipocytes to upregulate the production of ROS and proinflammatory cytokines, both of which lead to JNK1 activation, insulin resistance, and dysregulation of lipolysis. Therefore, PU.1 might be a mediator for obesity-induced adipose inflammation and insulin resistance.

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Section: Discussionmentioning

confidence: 55%

Adipocyte expression of PU.1 transcription factor causes insulin resistance through upregulation of inflammatory cytokine gene expression and ROS production

Lin

Pang

Chen

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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“…Inflammatory pathways are activated in response to the sensing of pathogens and danger signals through pattern recognition receptors, trigger nuclear signaling through the nuclear factor jB pathway, and culminate by maturation of pro-IL-1b to IL-1b (Takeuchi and Akira 2010). In addition to IL-1b, PU.1 regulates several other genes important for inflammation including secretory IL-1 receptor antagonist (IL1R1) (Smith et al 1998), IL-18 (IL18) (Kim et al 1999), the IL-12 p40 subunit (IL12B) (Becker et al 2001), and not least, tumor necrosis factor (TNF) (Fukai et al 2009). Interestingly, PU.1 is implicated in transcriptional regulation of several pattern recognition molecules that trigger inflammation, including Toll-like receptor 4 (TLR4) (Rehli et al 2000;Roger et al 2005) and TLR9 (Schroder et al 2007).…”

Section: Regulation Of Genes Encoding Cytokines and Cytokine Receptormentioning

confidence: 99%

The Transcription Factor PU.1 is a Critical Regulator of Cellular Communication in the Immune System

Turkistany

DeKoter

2011

Arch. Immunol. Ther. Exp.

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PU.1 is an E26 transformation-specific family transcription factor that is required for development of the immune system. PU.1 functions at both early and late stages of lymphoid and myeloid differentiation. At least 110 direct target genes of PU.1 have been identified since its discovery in 1988. We used the published literature to determine if aspects of PU.1 function can be inferred from the identity of target genes that are directly activated. This analysis revealed that 61% of described PU.1 target genes encode extracellular proteins or transmembrane proteins, most of which are involved in cellular communication. The genes activated by PU.1 can be grouped into pathways based on function. Specific examples of cellular communication pathways regulated by PU.1 include (1) antibodies and antibody receptors, (2) cytokines and cytokine receptors regulating leukocyte growth and development, and (3) cytokines and cytokine receptors regulating inflammation. As a consequence of mutation or repression of the gene encoding PU.1, hematopoietic progenitors may be generated but there is a "failure to thrive" because they cannot interact with their environment. The loss of cellular communication caused by reduced PU.1 levels can lead to leukemia. In summary, PU.1 is a critical regulator of cellular communication in the immune system.

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“…For instance, in bone marrow-derived DCs, PU.1 up-regulates the expression of DC-characteristic genes, such as class II transactivator (CIITA), CD80, CD86, and IL-12 p40 [13,14], while suppressing the expression of Th2 cytokines, including IL-13 and IL-5 [15]. PU.1 regulates its target genes through epigenetic modifications, including histone deacetylation and DNA methylation [16,17]. Our previous study using an intestinal allograft model showed that compared with immature DCs, PU.1-silenced DCs had better and more stable effects in reducing the inflammatory response [18], and therefore, we aimed to establish stable mixed chimerism in a rat model of heterotopic intestinal transplantation (HIT) using simultaneous transfusion of PU.1-silenced DCs and donor-derived bone marrow cells without irradiation or other cytoreductive conditioning.…”

Section: Introductionmentioning

confidence: 99%

PU.1-Silenced Dendritic Cells Induce Mixed Chimerism and Alleviate Intestinal Transplant Rejection in Rats via a Th1 to Th2 Shift

Gao²,

Zhao³

et al. 2016

Cell Physiol Biochem

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Background/Aims: Intestinal transplantation is an effective treatment for end-stage bowel failure; however, graft rejection and the toxicity associated with non-specific immunosuppression are major limitations of this procedure. Studies have shown that mixed chimerism can produce post-transplantation immune tolerance. Here, we demonstrate that in rat intestinal transplantation, PU.1-silenced dendritic cells (DCs) plus bone marrow (BM) cell transfusion results in mixed chimerism, and we investigate the mechanisms responsible for the effects of mixed chimerism rejection. Methods: In a model of intestinal transplantation, male Brown Norway rats were the donors, and female Lewis rats were the recipients that were randomly divided into 4 groups: control, BM, BM-imDCs and BM-PU.1. The dynamic changes in graft morphology, rejection scoring and serum concentrations of Th1/Th2-related cytokines were investigated on postoperative days 0, 7, 14, 21, and 30. Results: The BM-PU.1 group had better graft health, milder pathologic injuries, and lower rejection grades compared with the other groups. The rates of mixed chimerism were significantly highest in the BM-PU.1 group and correlated with decreases in serum IL-2 and increases in serum IL-10. Conclusion: Transfusion of PU.1-silenced DCs and BM cells induces stable mixed chimerism and has the potential to reduce pathologic injuries via a pro-Th2 shift in the Th1/Th2 balance.

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Involvement of PU.1 in the transcriptional regulation of TNF-α

Cited by 23 publications

References 27 publications

Adipocyte expression of PU.1 transcription factor causes insulin resistance through upregulation of inflammatory cytokine gene expression and ROS production

Adipocyte expression of PU.1 transcription factor causes insulin resistance through upregulation of inflammatory cytokine gene expression and ROS production

The Transcription Factor PU.1 is a Critical Regulator of Cellular Communication in the Immune System

PU.1-Silenced Dendritic Cells Induce Mixed Chimerism and Alleviate Intestinal Transplant Rejection in Rats via a Th1 to Th2 Shift

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