EGF activates TTP expression by activation of ELK-1 and EGR-1 transcription factors

<p>Abstract</p> <p>Background</p> <p>Tristetraprolin (TTP) is a key mediator of processes such as inflammation resolution, the inhibition of autoimmunity and in cancer. It carries out this role by the binding and degradation of mRNA transcripts, thereby decreasing their half-life. Transcripts modulated by TTP encode proteins such as cytokines, pro-inflammatory agents and immediate-early response proteins. TTP can also modulate neoplastic phenotypes in many cancers. TTP is induced and functionally regulated by a spectrum of both pro- and anti-inflammatory cytokines, mitogens and drugs in a MAPK-dependent manner. So far the contribution of p38 MAPK to the regulation of TTP expression and function has been best described.</p> <p>Results</p> <p>Our results demonstrate the induction of the gene coding TTP (<it>ZFP36</it>) by EGF through the ERK1/2-dependent pathway and implicates the transcription factor ELK-1 in this process. We show that ELK-1 regulates <it>ZFP36 </it>expression by two mechanisms: by binding the <it>ZFP36 </it>promoter directly through ETS-binding site (+ 883 to +905 bp) and by inducing expression of EGR-1, which in turn increases <it>ZFP36 </it>expression through sequences located between -111 and -103 bp.</p> <p>Conclusions</p> <p>EGF activates TTP expression via ELK-1 and EGR-1 transcription factors.</p

Transcription factors Elk-1 and SRF are engaged in IL1-dependent regulation of ZC3H12A expression

<p>Abstract</p> <p>Background</p> <p>MCPIP is a novel CCCH zinc finger protein described as an RNase engaged in the regulation of immune responses. The regulation of expression of the gene coding for MCPIP - <it>ZC3H12A </it>is poorly explored.</p> <p>Results</p> <p>Here we report that the proinflammatory cytokine IL-1β rapidly induces the synthesis of MCPIP in primary monocyte-derived macrophages and HepG2 cells. This up-regulation takes place through the MAP kinase pathway and following activation of the transcription factor Elk-1. Using a <it>ZC3H12A </it>reporter construct we have shown that a <it>ZC3H12A </it>promoter region, stretching from -76 to +60, mediates activation by IL-1β. This region contains binding sites for Elk-1 and its partner SRF. Chromatin immunoprecipitation analysis confirms <it>in vivo </it>binding of both transcription factors to this region of the <it>ZC3H12A </it>promoter.</p> <p>Conclusions</p> <p>We conclude that the transcription factor Elk-1 plays an important role in the activation of <it>ZC3H12A </it>expression in response to IL-1β stimulation.</p

Iron in the Tumor Microenvironment—Connecting the Dots

Iron metabolism and tumor biology are intimately linked. Iron facilitates the production of oxygen radicals, which may either result in iron-induced cell death, ferroptosis, or contribute to mutagenicity and malignant transformation. Once transformed, malignant cells require high amounts of iron for proliferation. In addition, iron has multiple regulatory effects on the immune system, thus affecting tumor surveillance by immune cells. For these reasons, inconsiderate iron supplementation in cancer patients has the potential of worsening disease course and outcome. On the other hand, chronic immune activation in the setting of malignancy alters systemic iron homeostasis and directs iron fluxes into myeloid cells. While this response aims at withdrawing iron from tumor cells, it may impair the effector functions of tumor-associated macrophages and will result in iron-restricted erythropoiesis and the development of anemia, subsequently. This review summarizes our current knowledge of the interconnections of iron homeostasis with cancer biology, discusses current clinical controversies in the treatment of anemia of cancer and focuses on the potential roles of iron in the solid tumor microenvironment, also speculating on yet unknown molecular mechanisms

Sex hormones influence survival of patients with metastatic urothelial carcinoma undergoing immune checkpoint therapy

Introduction Clinical trials investigating efficacy of immune checkpoint inhibitors (ICI) revealed sex-specific divergent outcomes in urothelial cancer (UC), suggesting that sex hormones might play an important role in gender-specific dimorphisms of response upon ICI. However, further clinical investigations are still needed to understand the influence of sex hormones in UC. The aim of this study was to get further insights on the prognostic and predictive value of sex hormone levels in patients with metastatic UC (mUC) who underwent ICI. Material and methods Sex hormone levels of patients with mUC including luteinizing hormone (LH), follicle-stimulating hormone (FSH), LH/FSH ratio, prolactin, testosterone and 17β-estradiol (E2) were evaluated at baseline and during ICI at 6/8 weeks and 12/14 weeks. Results Twenty-eight patients (10 women, 18 men) with a median age of 70 years were included. Metastatic disease was confirmed in 21 patients (75%) after radical cystectomy while seven patients showed mUC at first diagnosis. Twelve patients (42.8%) received first line and 16 patients second line pembrolizumab. The objective response rate (ORR) was 39% (CR in 7%). The median progression-free survival (PFS) and overall survival (OS) was 5.5 and 20 months. Focusing on changes of sex hormone levels during ICI, a significant increase in FSH levels and decrease of the LH/FSH ratio was noticed in responders (p = 0.035), yet without sex-specific significance. When adjusted for sex and treatment line, a significant increase of FSH levels was confirmed in men during second line pembrolizumab. Focusing on baseline levels, LH/FSH ratio was significantly higher in female responders (p = 0.043) compared to non-responders. In women, increased LH levels and LH/FSH ratio were associated with better PFS (p = 0.014 for LH, p = 0.016 for LH/FSH ratio) and OS (p = 0.026 and p = 0.018). In male patients, increased E2 levels were linked with improved PFS (p < 0.001) and OS (p = 0.039). Conclusion Increased LH and LH/FSH values in women as well as high E2 levels in men were significant predictors of better survival. Elevated LH/FSH ratio was predictive of better response to ICI in women. These results show first clinical evidence of the potential role of sex hormones as prognostic and predictive biomarker in mUC. Further prospective analyses are needed to corroborate our findings

A chemokine network of T cell exhaustion and metabolic reprogramming in renal cell carcinoma

Renal cell carcinoma (RCC) is frequently infiltrated by immune cells, a process which is governed by chemokines. CD8+ T cells in the RCC tumor microenvironment (TME) may be exhausted which most likely influence therapy response and survival. The aim of this study was to evaluate chemokine-driven T cell recruitment, T cell exhaustion in the RCC TME, as well as metabolic processes leading to their functional anergy in RCC. Eight publicly available bulk RCC transcriptome collectives (n=1819) and a single cell RNAseq dataset (n=12) were analyzed. Immunodeconvolution, semi-supervised clustering, gene set variation analysis and Monte Carlo-based modeling of metabolic reaction activity were employed. Among 28 chemokine genes available, CXCL9/10/11/CXCR3, CXCL13/CXCR5 and XCL1/XCR1 mRNA expression were significantly increased in RCC compared to normal kidney tissue and also strongly associated with tumor-infiltrating effector memory and central memory CD8+ T cells in all investigated collectives. M1 TAMs, T cells, NK cells as well as tumor cells were identified as the major sources of these chemokines, whereas T cells, B cells and dendritic cells were found to predominantly express the cognate receptors. The cluster of RCCs characterized by high chemokine expression and high CD8+ T cell infiltration displayed a strong activation of IFN/JAK/STAT signaling with elevated expression of multiple T cell exhaustion-associated transcripts. Chemokinehigh RCCs were characterized by metabolic reprogramming, in particular by downregulated OXPHOS and increased IDO1-mediated tryptophan degradation. None of the investigated chemokine genes was significantly associated with survival or response to immunotherapy. We propose a chemokine network that mediates CD8+ T cell recruitment and identify T cell exhaustion, altered energy metabolism and high IDO1 activity as key mechanisms of their suppression. Concomitant targeting of exhaustion pathways and metabolism may pose an effective approach to RCC therapy

Ferritin H deficiency deteriorates cellular iron handling and worsens Salmonella typhimurium infection by triggering hyperinflammation

Iron is an essential nutrient for mammals as well as for pathogens. Inflammation-driven changes in systemic and cellular iron homeostasis are central for host-mediated antimicrobial strategies. Here, we studied the role of the iron storage protein ferritin H (FTH) for the control of infections with the intracellular pathogen Salmonella enterica serovar Typhimurium by macrophages. Mice lacking FTH in the myeloid lineage (LysM-Cre+/+Fthfl/fl mice) displayed impaired iron storage capacities in the tissue leukocyte compartment, increased levels of labile iron in macrophages, and an accelerated macrophage-mediated iron turnover. While under steady-state conditions, LysM-Cre+/+Fth+/+ and LysM-Cre+/+Fthfl/fl animals showed comparable susceptibility to Salmonella infection, i.v. iron supplementation drastically shortened survival of LysM-Cre+/+Fthfl/fl mice. Mechanistically, these animals displayed increased bacterial burden, which contributed to uncontrolled triggering of NF-κB and inflammasome signaling and development of cytokine storm and death. Importantly, pharmacologic inhibition of the inflammasome and IL-1β pathways reduced cytokine levels and mortality and partly restored infection control in iron-treated ferritin-deficient mice. These findings uncover incompletely characterized roles of ferritin and cellular iron turnover in myeloid cells in controlling bacterial spread and for modulating NF-κB and inflammasome-mediated cytokine activation, which may be of vital importance in iron-overloaded individuals suffering from severe infections and sepsis

Dietary lipids fuel GPX4-restricted enteritis resembling Crohn’s disease

Abstract: The increased incidence of inflammatory bowel disease (IBD) has become a global phenomenon that could be related to adoption of a Western life-style. Westernization of dietary habits is partly characterized by enrichment with the ω-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA), which entails risk for developing IBD. Glutathione peroxidase 4 (GPX4) protects against lipid peroxidation (LPO) and cell death termed ferroptosis. We report that small intestinal epithelial cells (IECs) in Crohn’s disease (CD) exhibit impaired GPX4 activity and signs of LPO. PUFAs and specifically AA trigger a cytokine response of IECs which is restricted by GPX4. While GPX4 does not control AA metabolism, cytokine production is governed by similar mechanisms as ferroptosis. A PUFA-enriched Western diet triggers focal granuloma-like neutrophilic enteritis in mice that lack one allele of Gpx4 in IECs. Our study identifies dietary PUFAs as a trigger of GPX4-restricted mucosal inflammation phenocopying aspects of human CD

On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver

Iron is an essential component of the erythrocyte protein hemoglobin and is crucial to oxygen transport in vertebrates. In the steady state, erythrocyte production is in equilibrium with erythrocyte removal1. In various pathophysiological conditions, however, erythrocyte life span is severely compromised, which threatens the organism with anemia and iron toxicity2,3. Here we identify an on-demand mechanism that clears erythrocytes and recycles iron. We show that Ly-6Chigh monocytes ingest stressed and senescent erythrocytes, accumulate in the liver via coordinated chemotactic cues, and differentiate to ferroportin 1 (FPN1)-expressing macrophages that can deliver iron to hepatocytes. Monocyte-derived FPN1+ Tim-4neg macrophages are transient, reside alongside embryonically-derived Tim-4high Kupffer cells, and depend on Csf1 and Nrf2. The spleen likewise recruits iron-loaded Ly-6Chigh monocytes, but these do not differentiate into iron-recycling macrophages due to the suppressive action of Csf2. Inhibiting monocyte recruitment to the liver leads to kidney and liver damage. These observations identify the liver as the primary organ supporting rapid erythrocyte removal and iron recycling and uncover a mechanism by which the body adapts to fluctuations in erythrocyte integrity

Effect of X-rays on Seedling Pigment, Biochemical Profile, and Molecular Variability in <i>Astrophytum</i> spp.

Cacti are important in agricultural economies and one of the most popular horticultural plant groups. The genus Astrophytum is one of the most valuable and desirable cacti for growers and collectors around the world. By selecting the appropriate breeding methods to induce variations in combination with modern biotechnology tools for rapid change detection, it is possible to meet the challenges of the modern world in creating new variability in plants. However, there exists a lack of research concerning the impact of ionizing radiation on cacti. The aim of the study was to assess the effects of X-rays at different doses (0 Gy—control, 15, 20, 25, and 50 Gy) on the dynamics of seed germination in vitro, changes in the color of seedlings, biochemical changes in the content of metabolites and changes at the molecular level in Astrophytum spp. ‘Purple’. A significant effect of X-rays on the induction of genetic variation was observed. Remarkably high polymorphism rates were observed, ranging from 59.09% for primer S12 to a full 100.0% for S3 and S8, as determined by the SCoT (Start-Codon-Targeted) marker. In addition, a large variation in the content of plant pigments (anthocyanins, carotenoids, chlorophyll a, and chlorophyll b) was noted. Additionally, discernible alterations in the color of the tested cactus seedlings, assessed by the RHSCC catalog, were attributed to the impact of ionizing radiation. These findings hold promise for the application of radiomutation breeding in acquiring new cactus cultivars