bims-stacyt 2023-11-05 papers

Peptides. 2023 Oct 31. pii: S0196-9781(23)00177-8. [Epub ahead of print] 171112

Growth differentiation factor-15 stimulates the synthesis of corticotropin-releasing factor in hypothalamic 4B cells.

Mizuki Tasso, Kazunori Kageyama, Yasumasa Iwasaki, Yutaka Watanuki, Kanako Niioka, Shinobu Takayasu, Makoto Daimon.

Growth differentiation factor-15 (GDF15) is a stress-activated cytokine that regulates cell growth and inflammatory and stress responses. We previously reported the role and regulation of GDF15 in pituitary corticotrophs. Dexamethasone increases Gdf15 gene expression levels and production. GDF15 suppresses adrenocorticotropic hormone synthesis in pituitary corticotrophs and subsequently mediates the negative feedback effect of glucocorticoids. Here, we analyzed corticotropin-releasing factor (Crf) promoter activity in hypothalamic 4B cells transfected with promoter-driven luciferase reporter constructs. The effects of time and GDF15 concentration on Crf mRNA levels were analyzed using quantitative real-time polymerase chain reaction. Glial cell-derived neurotrophic factor family receptor α-like (GFRAL) protein is expressed in 4B cells. GDF15 increased Crf promoter activity and Crf mRNA levels in 4B cells. The protein kinase A and C pathways also contributed to the GDF15-induced increase in Crf gene expression. GDF15 stimulates GFRAL, subsequently increasing the phosphorylation of AKT, an extracellular signal-related kinase, and the cAMP response element-binding protein. Therefore, GDF15-dependent pathways may be involved in regulating Crf expression under stressful conditions in hypothalamic cells.

Keywords: corticotropin-releasing factor; growth differentiation factor-15; hypothalamus; stress

DOI: https://doi.org/10.1016/j.peptides.2023.171112

Cell Death Dis. 2023 Oct 28. 14(10): 703

Targeting cancer-associated adipocyte-derived CXCL8 inhibits triple-negative breast cancer progression and enhances the efficacy of anti-PD-1 immunotherapy.

Renhong Huang, Zheng Wang, Jin Hong, Jiayi Wu, Ou Huang, Jianrong He, Weiguo Chen, Yafen Li, Xiaosong Chen, Kunwei Shen.

Cancer-associated adipocytes (CAAs), one of the primary stromal components, exhibit intimate crosstalk and release multiple cell factors mediating local and systemic biological effects. However, the role of CAAs in the regulation of systemic immune responses and their potential value in the clinical treatment of triple-negative breast cancer (TNBC) are not well described. Transcriptome sequencing was performed on CAA and normal adipocyte (NA) tissues isolated from surgically resected samples from TNBC patients and healthy controls. Cytokines, including C-X-C motif chemokine ligand 8 (CXCL8, also known as IL-8), secreted from NAs and CAAs were compared by transcriptome sequencing and enzyme-linked immunosorbent assay (ELISA). Proliferation, migration and invasion assays were employed to analyze the role of CAAs and CAA-derived CXCL8 (macrophage inflammatory protein-2 (MIP2) as a functional surrogate in mice). TNBC syngraft models were established to evaluate the curative effect of targeting CXCL8 in combination with anti-PD-1 therapies. Real-time quantitative polymerase chain reaction (RT-qPCR), western blotting (WB), polymerase chain reaction (PCR) array, flow cytometry, immunohistochemistry (IHC), and immunofluorescence (IF) were applied to analyze immune cell infiltration and epithelial-mesenchymal transition (EMT) markers. Specifically, we demonstrated that CAAs and CAA-derived CXCL8 played important roles in tumor growth, EMT, metastasis and tumor immunity suppression. CAA-derived CXCL8 remodeled the tumor immune microenvironment not only by suppressing CD4+ T and CD8+ T immune cell infiltration but also by upregulating CD274 expression in TNBC. The combination of targeting the CXCL8 pathway and blocking the PD-1 pathway synergistically increased the tumor immune response and inhibited tumor progression. Thus, our results highlight the molecular mechanisms and translational significance of CAAs in tumor progression and immune ecosystem regulatory effects and provide a better understanding of the potential clinical benefit of targeting CAA-derived CXCL8 in antitumor immunity and as a new therapeutic moiety in TNBC.

DOI: https://doi.org/10.1038/s41419-023-06230-z

Front Immunol. 2023 ;14 1279495

Landscape of tumor and immune system cells-derived exosomes in lung cancer: mediators of antitumor immunity regulation.

Alejandro Castillo-Peña, Sonia Molina-Pinelo.

The immune system plays a critical role in cancer, including lung cancer, which is the leading cause of cancer-related deaths worldwide. Immunotherapy, particularly immune checkpoint blockade, has revolutionized the treatment of lung cancer, but a large subset of patients either do not respond or develop resistance. Exosomes, essential mediators of cell-to-cell communication, exert a profound influence on the tumor microenvironment and the interplay between cancer and the immune system. This review focuses on the role of tumor-derived exosomes and immune cells-derived exosomes in the crosstalk between these cell types, influencing the initiation and progression of lung cancer. Depending on their cell of origin and microenvironment, exosomes can contain immunosuppressive or immunostimulatory molecules that can either promote or inhibit tumor growth, thus playing a dual role in the disease. Furthermore, the use of exosomes in lung cancer immunotherapy is discussed. Their potential applications as cell-free vaccines and drug delivery systems make them an attractive option for lung cancer treatment. Additionally, exosomal proteins and RNAs emerge as promising biomarkers that could be employed for the prediction, diagnosis, prognosis and monitoring of the disease. In summary, this review assesses the relationship between exosomes, lung cancer, and the immune system, shedding light on their potential clinical applications and future perspectives.

Keywords: exosome; immune cell; immunotherapy; lung cancer; tumor microenvironment

DOI: https://doi.org/10.3389/fimmu.2023.1279495

Clin Physiol Funct Imaging. 2023 Oct 29.

ENHANCED INTERLEUKIN-6 IN HUMAN ADIPOSE TISSUE VEIN AFTER SPRINT EXERCISE: RESULTS FROM A PILOT STUDY.

Mona Esbjörnsson, Barbara Norman, Moa Persson, Amarjit Saini, Jens Bülow, Eva Jansson.

BACKGROUND: Low volume sprint exercise is likely to reduce body fat. Interleukin (IL-6) may mediate this by increasing adipose tissue lipolysis. Therefore, the exchange of adipose tissue (AT) IL-6 and glycerol, a marker of lipolysis, was examined in 10 healthy subjects performing three 30-s all-out sprints.
METHODS: Blood samples were obtained from brachial artery (a) and a superficial subcutaneous vein (v) on the anterior abdominal wall up to 9 min after the last sprint and analysed for IL-6 and glycerol.
RESULTS: Arterial IL-6 increased 2-fold from rest to last sprint. AT venous IL-6 increased 15-fold from 0.4±0.4 at rest to 7.0±4 pg x mL-1 (P< 0.0001) and AT v-a difference increased 45-fold from 0.12±0.3 to 6.0±5 pg x mL-1 (P< 0.0001) 9 min after last sprint. Arterial glycerol increased 2.5-fold from rest to 9 min post sprint 1 (P< 0.0001) and was maintained during the exercise period. AT venous and v-a difference of glycerol increased 2-fold from rest to 9 min post sprint 1 (P< 0.0001 and P= 0.01, respectively), decreased until 18 min post sprint 2 (P< 0.001 and P< 0.0001), and then increased again until 9 min after last sprint (both P< 0.01).
CONCLUSIONS: The concurrent increase in venous IL-6 and glycerol in adipose tissue after last sprint is consistent with an IL-6 induced lipolysis in adipose tissue. Glycerol data also indicated an initial increase in lipolysis after sprint 1 that was unrelated to IL-6. Increased IL-6 in adipose tissue may therefore complement other sprint exercise-induced lipolytic agents. This article is protected by copyright. All rights reserved.

Keywords: body weight; glycerol; high intensity interval training; lactate; lipolysis subcutaneous white adipose tissue

DOI: https://doi.org/10.1111/cpf.12863