White adipose tissue inflammation is linked with increased aromatase gene expression and estrogen production, a major risk factor for breast cancer in obese postmenopausal women. TNF-α, a proinflammatory cytokine, is a key driver of aromatase promoter I.4-mediated expression in adipose tissue. In this study, we have shown that IL-10, an anti-inflammatory cytokine, suppressed both TNF-α-stimulated human aromatase reporter-luciferase (hARO-Luc) expression in mouse bone marrow mesenchymal stromal cells and aromatase gene expression in human breast adipose stromal cells (ASCs). IL-10 blocked TNF-α-stimulated ERK1/2 activation in ASCs, suggesting an inhibitory effect through the MAPK signaling pathway. The links among obesity, IL-10, and aromatase were confirmed in ovariectomized (OVX) hARO-Luc mice, where increased adiposity was associated with upregulation of aromatase reporter activity and reduced IL-10 level in the mammary fat pad. OVX mice also exhibited changes in gut microbiota, similar to that in obese women, indicating altered immune function. In summary, our results suggest that increased adiposity, induced by the lack of ovarian hormones, results in enhanced expression of aromatase in mammary adipose tissue, mediated by reduction in local IL-10. These findings may bring new insights into the mechanisms involved in the development of postmenopausal breast cancer, as well as novel approaches for prevention.-Martínez-Chacón, G., Brown, K. A., Docanto, M. M., Kumar, H., Salminen, S., Saarinen, N., Mäkelä, S. IL-10 suppresses TNF-α-induced expression of human aromatase gene in mammary adipose tissue.

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Oxidative stress has been attributed both a key pathogenic and rescuing role in cerebral malaria (CM). In a Plasmodium berghei ANKA murine model of CM, host redox signaling and functioning were examined during the course of neurological damage. Host antioxidant defenses were early altered at the transcriptional level indicated by the gradually diminished expression of superoxide dismutase-1 (sod-1), sod-2, sod-3 and catalase genes. During severe disease, this led to the dysfunctional activity of superoxide dismutase and catalase enzymes in damaged brain regions. Vitagene associated markers (heat shock protein 70 and thioredoxin-1) also showed a decaying expression pattern that paralleled reduced expression of the transcription factors Parkinson disease 7, Forkhead box O 3 and X-box binding protein 1 with a role in preserving brain redox status. However, the oxidative stress markers reactive oxygen/nitrogen species were not accumulated in the brains of CM mice and redox proteomics and immunohistochemistry failed to detect quantitative or qualitative differences in protein carbonylation. Thus, the loss of antioxidant capacity was compensated for in all cerebral regions by progressive upregulation of heme oxygenase-1, and in specific regions by early glutathione peroxidase-1 induction. This study shows for the first time a scenario of cooperative glutathione peroxidase and heme oxygenase-1 upregulation to suppress superoxide dismutase, catalase, heat shock protein-70 and thioredoxin-1 downregulation effects in experimental CM, counteracting oxidative damage and maintaining redox equilibrium. Our findings reconcile the apparent inconsistency between the lack of oxidative metabolite build up and reported protective effect of antioxidant therapy against CM.

Methionine 1 (M1)-linked ubiquitination plays a key role in the regulation of inflammatory nuclear factor-jB (NF-jB) signalling and is important for clearance of pathogen infection in Drosophila melanogaster. M1-linked ubiquitin (M1-Ub) chains are assembled by the linear ubiquitin E3 ligase (LUBEL) in flies. Here, we have studied the role of LUBEL in sterile inflammation induced by different types of cellular stresses. We have found that the LUBEL catalyses formation of M1-Ub chains in response to hypoxic, oxidative and mechanical stress conditions. LUBEL is shown to be important for flies to survive low oxygen conditions and paraquat-induced oxidative stress. This protective action seems to be driven by stress-induced activation of the NF-jB transcription factor Relish via the immune deficiency (Imd) pathway. In addition to LUBEL, the intracellular mediators of Relish activation, including the transforming growth factor activating kinase 1 (Tak1), Drosophila inhibitor of apoptosis (IAP) Diap2, the IjB kinase c (IKKc) Kenny and the initiator caspase Death-related ced-3/Nedd2-like protein (Dredd), but not the membrane receptor peptidoglycan recognition protein (PGRP)-LC, are shown to be required for sterile inflammatory response and survival. Finally, we showed that the stress-induced upregulation of M1-Ub chains in response to hypoxia, oxidative and mechanical stress is also induced in mammalian cells and protects from stress-induced cell death. Taken together, our results suggest that M1-Ub chains are important for NF-jB signalling in inflammation induced by stress conditions often observed in chronic inflammatory diseases and cancer.Abbreviations AMP, antimicrobial peptide; daGal4, daughterless-Gal4; DAMP, danger-associated molecular pattern; Diap, Drosophila inhibitor of apoptosis; Dif, Dorsal-related immunity factor; Dredd, death-related ced-3/Nedd2-like protein; DUB, deubiquitinating enzyme; Fadd, fas-associated death domain; HIF, hypoxia-inducible factor; HOIL-1L, heme-oxidised iron-responsive element-binding protein 2 ubiquitin ligase-1L; HOIP, HOIL-1interacting protein; IKK, IjB kinase; Imd, immune deficiency; LDD, linear ubiquitin chain-determining domain; LUBAC, linear ubiquitin chain assembly complex; LUBEL, linear ubiquitin E3 ligase; NF-jB, nuclear factor j-light-chain enhancer of activated B cells; NZF, npl4 zinc finger; PAMP, pathogen-associated molecular pattern; PGRP, peptidoglycan recognition protein; PIM, PUB-interacting motif; PNG, peptide N-glycanase; PRR, pattern-recognition receptor; PUB, UBA or UBX-containing protein; RBR, RING in between RING; RING, really interesting new gene; SAMP, stress-associated molecular pattern; SHARPIN, SH3 and multiple ankyrin repeat domains protein (SHANK)-associated RBCK1 homology (RH) domain-interacting protein; Sima, similar; Tab2, transforming growth factor-b-activated kinase 1 binding protein 2; Tak1, transforming growth factor activating kinase; TGF, transforming growth factor; TNF, tumour necrosis factor; TRAIL, TNF-related apoptosis-inducing ligand; TUB...

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No abstract

Methionine 1 (M1)-linked ubiquitination plays a key role in the regulation of inflammatory nuclear factor-κB (NF-κB) signalling and is important for clearance of pathogen infection in Drosophila melanogaster. M1-linked ubiquitin (M1-Ub) chains are assembled by the linear ubiquitin E3 ligase (LUBEL) in flies. Here, we have studied the role of LUBEL in sterile inflammation induced by different types of cellular stresses. We have found that LUBEL catalyses formation of M1-Ub chains in response to hypoxic, oxidative and mechanical stress conditions. LUBEL is shown to be important for flies to survive low oxygen conditions and paraquat-induced oxidative stress. This protective action seems to be driven by stress-induced activation of the NF-κB transcription factor Relish via the Immune deficiency (Imd) pathway. In addition to LUBEL, the intracellular mediators of Relish activation, including the Drosophila inhibitor of apoptosis (IAP) Diap2, the IκB kinase γ (IKKγ) Kenny and the initiator caspase Death-related ced-3/Nedd2-like protein (Dredd), but not the membrane receptor peptidoglycan recognition protein (PGRP)-LC, are shown to be required for sterile inflammatory response and survival. Finally, we showed that the stress-induced upregulation of M1-Ub chains in response to hypoxia, oxidative and mechanical stress is also induced in mammalian cells. Taken together, our results suggest that M1-Ub chains are important for NF-κB signalling in inflammation induced by stress conditions often observed in chronic inflammatory diseases and cancer.

Obesity is an important risk factor for the most common type of breast cancer, i.e., estrogen‐dependent postmenopausal breast cancer. Obesity‐related inflammation, defined by enhanced tissue macrophage infiltration and increased levels of proinflammatory factors, stimulates estrogen production and, in turn, promotes tumor formation and progression. The augmented inflammatory milieu activating aromatase expression, the rate‐limiting enzyme for estrogen synthesis, is suggested to be the major mechanism behind the increased risk for breast cancer. The regulation of aromatase (CYP19A1) gene expression in breast tissue is complex and not fully understood. This study focuses on the role of CCL2, a macrophage recruiter often overexpressed in the obese and cancerous breast tissue, on the aromatase expression in mammary adipose tissue. We utilized mammary adipose tissue explants obtained from female hARO‐Luc aromatase reporter mice and cultured primary human breast adipose stromal cells (hASCs). In tissue explants, aromatase expression was measured by quantification of luciferase reporter activity, while in cultured hASCs, qPCR was used to examine expression of CYP19A1 and its specific promoter I.4 and II transcripts. Both, in mammary adipose tissue and in hASCs, CCL2 induced aromatase expression via the distal promoter I.4. Moreover, inhibitors of CCL2 receptor and MAPKs pathway, ERK1/2, blocked CCL2–induced CYP19A1 and PI.4 mRNA expression. In conclusion, these findings indicate that CCL2, an intrinsic pro‐inflammatory chemokine in adipose tissue, may stimulate aromatase expression and play an important role in controlling estrogen biosynthesis in the breast adipose stroma.Support or Funding InformationThis research is supported by the University of Turku Graduate School, the Finnish Cultural Foundation, the Turun yliopistosäätiö and the Institute of Biomedicine, University of TurkuThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.