ATF4 is directly recruited by TLR4 signaling and positively regulates TLR4-trigged cytokine production in human monocytes

Zhang, Chunyan; Bai, Nan; Chang, Antao; Zhang, Zhuhong; Yin, Jing; Shen, Wenzhi; Tian, Yaping; Xiang, Rong; Liu, Chenghu

doi:10.1038/cmi.2012.57

Cited by 79 publications

(63 citation statements)

References 64 publications

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“…Previous studies have shown that ATF4 is regulated at the post-transcriptional level [31]. In our study, we found that ATF4 mRNA was induced in many human cell lines by 60 Coγ radiation.…”

Section: Discussionsupporting

confidence: 64%

Up-Regulated ATF4 Expression Increases Cell Sensitivity to Apoptosis in Response to Radiation

Zong

Feng

Cheng

et al. 2017

Cell Physiol Biochem

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Background/Aims: Activating transcription factor 4 (ATF4) is a member of the activating transcription factor family which regulates the expression of genes involved in amino acid metabolism, redox homeostasis and ER stress responses. ATF4 is also over-expressed in human solid tumors, although its effect on responsiveness to radiation is largely unexplored. Methods: Real-time PCR was used to detect ATF4 mRNA levels in cells treated with different doses of ⁶⁰Coγ radiation. Cell viability was assayed using a cell counting kit. The cell cycle was analyzed using flow cytometry, and cell apoptosis was assayed using Annexin V-PI double labeling. Small interfering RNA (siRNA) against ATF4 was transfected into ECV304 cells using Lipofectamine 2000. An ATF4 over-expression plasmid (p-ATF4-CGN) was transfected into HEK293 cells that endogenously expressed low levels of ATF4. The levels of intracellular reactive oxygen species (ROS) were measured using CM-H2DCFDA as a probe. Results: ATF4 mRNA and protein expression levels were higher after radiation and increased in a dose- and time-dependent manner in AHH1 lymphoblast cells (P < 0.05). An increase in ATF4 levels was also observed after radiation in primary murine spleen cells, human endothelial ECV304 cells, human liver LO2 cells, breast cancer MCF7 cells, and human hepatocellular carcinoma HEPG2 cells. No change was observed in human embryonic kidney 293 (HEK293) cells. Over-expressing ATF4 in HEK293 cells inhibited cell proliferation, increased cell apoptosis and significantly increased the proportion of cells in G1 phase. Conversely, when ATF4 expression was knocked down using siRNA in ECV304 cells, it protected the cells from radiation-induced apoptosis. These findings suggest that ATF4 may play a role in radiation-induced cell killing by inhibiting cell proliferation and promoting cell apoptosis. Conclusions: In this study, we found that radiation up-regulated the expression of ATF4. We used ATF4 knockdown and over-expression systems to show that ATF4 may play a role in radiation-induced cellular apoptosis.

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“…Previous studies have shown that ATF4 is regulated at the post-transcriptional level [31]. In our study, we found that ATF4 mRNA was induced in many human cell lines by 60 Coγ radiation.…”

Section: Discussionsupporting

confidence: 64%

Up-Regulated ATF4 Expression Increases Cell Sensitivity to Apoptosis in Response to Radiation

Zong

Feng

Cheng

et al. 2017

Cell Physiol Biochem

View full text Add to dashboard Cite

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“…Limited studies have examined the role of ATF4 downstream of PRR. ATF4 was found to contribute to cytokine secretion upon acute TLR4 stimulation (49). In contrast, upon pre-stimulation of macrophages through TLR4, TRIF-dependent signaling led to the downregulation of the ATF4-CHOP branch of the unfolded protein response (50).…”

Section: Discussionmentioning

confidence: 99%

Twist1 and Twist2 Contribute to Cytokine Downregulation following Chronic NOD2 Stimulation of Human Macrophages through the Coordinated Regulation of Transcriptional Repressors and Activators

Zheng

Hedl

Abraham

2015

The Journal of Immunology

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Proper regulation of microbial-induced cytokines is critical to intestinal immune homeostasis. Acute stimulation of nucleotide-binding oligomerization domain 2 (NOD2), the Crohn’s disease–associated sensor of bacterial peptidoglycan, induces cytokines. However, chronic NOD2 stimulation in macrophages decreases cytokines upon pattern recognition receptor (PRR) restimulation; cytokine attenuation to PRR stimulation is similarly observed in intestinal macrophages. The role for the transcriptional repressors Twist1 and Twist2 in regulating PRR-induced cytokine outcomes is poorly understood and has not been reported for NOD2. We found that Twist1 and Twist2 were required for optimal cytokine downregulation during acute and, particularly, chronic NOD2 stimulation of human macrophages. Consistently, Twist1 and Twist2 expression was increased after chronic NOD2 stimulation; this increased expression was IL-10 and TGF-β dependent. Although Twist1 and Twist2 did not coregulate each other’s expression, they cooperated to enhance binding to cytokine promoters after chronic NOD2 stimulation. Moreover, Twist1 and Twist2 contributed to enhance expression and promoter binding of the proinflammatory inhibitor c-Maf and the transcriptional repressor Bmi1. Restoring c-Maf and Bmi1 expression in Twist-deficient macrophages restored NOD2-induced cytokine downregulation. Furthermore, with chronic NOD2 stimulation, Twist1 and Twist2 contributed to the decreased expression and cytokine promoter binding of the transcriptional activators activating transcription factor 4, C/EBPα, Runx1, and Runx2. Knockdown of these transcriptional activators in Twist-deficient macrophages restored cytokine downregulation after chronic NOD2 stimulation. Finally, NOD2 synergized with additional PRRs to increase Twist1 and Twist2 expression and Twist-dependent pathways. Therefore, after chronic NOD2 stimulation Twist1 and Twist2 coordinate the regulation of both transcriptional activators and repressors, thereby mediating optimal cytokine downregulation.

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“…It has been shown previously that IEC express low levels of TLR4 and respond poorly to LPS in terms of IL-8 secretion and NF-B activation (58). On the other hand, monocytic cells have been shown to express TLR1 to -10, MyD88, and TRIF transcripts and are often one of the primary sources of proinflammatory cytokines (59). For monocytic THP-1 cells, a distinct pattern of expression of the cytokines CXCL1 and IL-8 emerged, with EPEC inducing low expression levels compared to those with EcN (Fig.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-8, CXCL1, and MicroRNA miR-146a Responses to Probiotic Escherichia coli Nissle 1917 and Enteropathogenic E. coli in Human Intestinal Epithelial T84 and Monocytic THP-1 Cells after Apical or Basolateral Infection

et al. 2016

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ATF4 is directly recruited by TLR4 signaling and positively regulates TLR4-trigged cytokine production in human monocytes

Cited by 79 publications

References 64 publications

Up-Regulated ATF4 Expression Increases Cell Sensitivity to Apoptosis in Response to Radiation

Up-Regulated ATF4 Expression Increases Cell Sensitivity to Apoptosis in Response to Radiation

Twist1 and Twist2 Contribute to Cytokine Downregulation following Chronic NOD2 Stimulation of Human Macrophages through the Coordinated Regulation of Transcriptional Repressors and Activators

Interleukin-8, CXCL1, and MicroRNA miR-146a Responses to Probiotic Escherichia coli Nissle 1917 and Enteropathogenic E. coli in Human Intestinal Epithelial T84 and Monocytic THP-1 Cells after Apical or Basolateral Infection

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