Hypomorphic ADAM17(ex/ex) mice showed defects in mucosal regeneration due to inefficient enhanced GFR shedding. ADAM17 is the main sheddase of interleukin-6 receptor (IL-6R) to induce IL-6 trans-signaling. However, serum levels of soluble murine IL-6R were not reduced in ADAM17(ex/ex) mice, and murine ADAM17 was not the major sheddase of murine IL-6R. Shedding of murine IL-6R by murine ADAM17 was rescued in chimeric murine IL-6R proteins containing any extracellular domain but not the transmembrane and intracellular domain of human IL-6R. Apoptosis is a physiological stimulus of ADAM17-mediated shedding of human IL-6R. Even though apoptosis induced IL-6R shedding in mice, the responsible protease was identified as ADAM10. ADAM10 also was identified as protease responsible for ionomycin-induced shedding of murine and human IL-6R. However, in ADAM10-deficient murine embryonic fibroblasts, compensatory shedding of human IL-6R was mediated by ADAM17, but loss of ADAM10-mediated shedding of murine IL-6R was compensated by an as-yet-unidentified protease. Finally, we identified physiological purinergic P2X7 receptor stimulation as a novel inducer of murine and human IL-6R shedding solely mediated by ADAM10. In conclusion, we describe an unexpected species specificity of ADAM10 and ADAM17 and identified ADAM10 as novel inducible sheddase of IL-6R in mice and humans, which might have consequences for the interpretation of phenotypes from ADAM17- and ADAM10-deficient mice.
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http://dx.doi.org/10.1074/jbc.M111.229393 | DOI Listing |
Neuromolecular Med
January 2025
Department of Rehabilitation Medicine, The Affiliated Jiangning Hospital of Nanjing Medical University, No. 168 Gushan Road, Dongshan Street, Jiangning District, Nanjing, 211199, Jiangsu, China.
Muscle atrophy in pathological or diseased muscles arises from an imbalance between protein synthesis and degradation. Elevated levels of interleukin-6 (IL-6) are a hallmark of ischemic stroke and have been associated with muscle atrophy in certain pathological contexts. However, the mechanisms by which IL-6 induces muscle atrophy in the context of stroke remain unclear.
View Article and Find Full Text PDFCell Mol Immunol
January 2025
National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark.
Although interleukin (IL)-6 is considered immunosuppressive and tumor-promoting, emerging evidence suggests that it may support antitumor immunity. While combining immune checkpoint inhibitors (ICIs) and radiotherapy in patients with pancreatic cancer (PC) has yielded promising clinical results, the addition of an anti-IL-6 receptor (IL-6R) antibody has failed to elicit clinical benefits. Notably, a robust TGFβ-specific immune response at baseline in PC patients treated solely with ICIs and radiotherapy correlated with improved survival.
View Article and Find Full Text PDF3 Biotech
December 2024
Hainan Vocational University of Science and Technology, College of Medicine, No.18 Qiongshan Avenue, Meilan District, Haikou, 571100 Hainan People's Republic of China.
This study investigated the role of swimming exercise in regulating melanoma tumour growth and glycolysis in cancer cells, the specific mechanism involved was also studied. In our study, a murine melanoma tumour model was established to assess the impact of swimming on tumour growth. The mRNA and protein expressions were assessed using qRT-PCR, western blot, and IHC.
View Article and Find Full Text PDFMol Med Rep
February 2025
Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical University, Bengbu, Anhui 233030, P.R. China.
The occurrence of epilepsy is a spontaneous and recurring process due to abnormal neuronal firing in the brain. Epilepsy is understood to be caused by an imbalance between excitatory and inhibitory neurotransmitters in the neural network. The close association between astrocytes and synapses can regulate the excitability of neurons through the clearance of neurotransmitters.
View Article and Find Full Text PDFCell Signal
January 2025
Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Wenzhou Medical University, 325000 Wenzhou, Zhejiang, China. Electronic address:
Background: The mechanisms involved in the hyperlipidemia-associated acute pancreatitis (HLAP) is not yet fully understood.
Aims: To investigate the role of P38MAPK (mitogen-activated protein kinases) and oxidative stress in the pathogenesis of HLAP.
Methods: In AP (acute pancreatitis) patients, the GEO database retrieved gene expression profiles of cytokines, MAPK14, nuclear factor kappa B subunit 1 (NF-κB 1) and superoxide dismutase 2 (SOD 2).
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