We found recently that TNF-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible-14 (Fn14) by virtue of their strong capability to reduce the freely available cytoplasmic pool of TNFR-associated factor (TRAF)2 and cellular inhibitors of apoptosis (cIAPs) antagonize the functions of these molecules in TNFR1 signaling, resulting in sensitization for apoptosis and inhibition of classical NF-κB signaling. In this study, we demonstrate that priming of cells with TWEAK also interferes with activation of the classical NF-κB pathway by CD40. Likewise, there was strong inhibition of CD40 ligand (CD40L)-induced activation of MAPKs in TWEAK-primed cells. FACS analysis and CD40L binding studies revealed unchanged CD40 expression and normal CD40L-CD40 interaction in TWEAK-primed cells. CD40L immunoprecipitates, however, showed severely reduced amounts of CD40 and CD40-associated proteins, indicating impaired formation or reduced stability of CD40L-CD40 signaling complexes. The previously described inhibitory effect of TWEAK on TNFR1 signaling has been traced back to reduced activity of the TNFR1-associated TRAF2-cIAP1/2 ubiquitinase complex and did not affect the stability of the immunoprecipitable TNFR1 receptor complex. Thus, the inhibitory effect of TWEAK on CD40 signaling must be based at least partly on other mechanisms. In line with this, signaling by the CD40-related TRAF2-interacting receptor TNFR2 was also attenuated but still immunoprecipitable in TWEAK-primed cells. Collectively, we show that Fn14 activation by soluble TWEAK impairs CD40L-CD40 signaling complex formation and inhibits CD40 signaling and thus identify the Fn14-TWEAK system as a potential novel regulator of CD40-related cellular functions.
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http://dx.doi.org/10.4049/jimmunol.1202899 | DOI Listing |
Brain Res Bull
January 2025
Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China. Electronic address:
Cognitive dysfunction has become the second leading cause of death among the diabetic patients. In pre-diabetic stage, blood-brain barrier (BBB) injury occurs and induced the microvascular complications of diabetes, especially, diabetes-associated cognitive dysfunction (DACD). Endothelial cells are the major component of BBB, on which the increased expression of CD40 could mediate BBB dysfunction in diabetics.
View Article and Find Full Text PDFIntroduction: Inflammatory proteins have the potential to be used as therapeutic targets for inflammatory bowel disease (IBD).
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J Hazard Mater
January 2025
College of Plant Protection, Shandong Agricultural University, Taian, Shandong 271018, China. Electronic address:
Previous research on cadmium (Cd) focused on toxicity, neglecting hormesis and its mechanisms. In this study, pakchoi seedlings exposed to varying soil Cd concentrations (CK, 5, 10, 20, 40 mg/kg) showed an inverted U-shaped growth trend (hormesis characteristics): As Cd concentration increases, biomass exhibited hormesis character (Cd5) and then disappear (Cd40). ROS levels rose in both Cd treatments, with Cd5 being intermediate between CK and Cd40.
View Article and Find Full Text PDFInt Immunopharmacol
January 2025
Hunan Engineering Research Center of Livestock and Poultry Health Care, College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China. Electronic address:
Intestinal injury of weaned piglets often leads to reduced immunity, diarrhea and growth retardation, resulting in significant economic losses to agriculture. Betulinic acid (BA) is a natural plant-derived active ingredient with multiple pharmacological activities including immune modulation and anti-inflammatory. This study was aimed to investigate the potential mechanism that BA as a feed additive mitigated lipopolysaccharide (LPS)-induced intestinal injury in piglets.
View Article and Find Full Text PDFNature
January 2025
Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Tertiary lymphoid structures (TLSs) are de novo ectopic lymphoid aggregates that regulate immunity in chronically inflamed tissues, including tumours. Although TLSs form due to inflammation-triggered activation of the lymphotoxin (LT)-LTβ receptor (LTβR) pathway, the inflammatory signals and cells that induce TLSs remain incompletely identified. Here we show that interleukin-33 (IL-33), the alarmin released by inflamed tissues, induces TLSs.
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