Estrogen regulation of inflammatory responses has broad physiological and pathological consequences. However, the molecular mechanism of estrogen regulation of inflammation is still poorly understood. In this study, we report that activation of both STAT-1 and NF-kappaB signaling is essential for Con A-induced inducible NO synthase (iNOS) and NO in murine splenocytes. Estrogen enhances STAT-1 DNA-binding activity without increasing the expression of phosphorylated and total STAT-1 protein. We have recently reported that estrogen blocks the nuclear expression of NF-kappaB p65 and modifies nuclear NF-kappaBp50. Here, we demonstrated that both nuclear STAT-1 and NF-kappaB are modified by serine protease-mediated proteolysis, which resulted in altered STAT-1 and NF-kappaB activity/signaling in splenocytes from estrogen-treated mice. Inhibition of serine protease activity with 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF) restores the nuclear expression of full-length STAT-1 and NF-kappaB proteins, and resulted in decreased STAT-1 DNA-binding activity and formation of NF-kappaB p65/p50 binding complexes in nuclei of splenocytes from estrogen-treated mice. Consequently, there is significantly decreased iNOS and IFN-gamma production in AEBSF-treated splenocytes from estrogen-treated mice, which suggests a positive regulatory role of truncated STAT-1 and/or NF-kappaB. Interestingly, there is increased production of MCP-1 in STAT-1 or NF-kappaB small interfering RNA-transfected cells, as well as in AEBSF-treated splenocytes from estrogen-treated mice. These data suggest a differential role of truncated STAT-1 and NF-kappaB in regulation of various inflammatory molecules in splenocytes from estrogen-treated mice. Together, our data reveal a novel molecular mechanism of estrogen-mediated promotion of inflammatory responses, which involves posttranslational modification of STAT-1 and NF-kappaB proteins.
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http://dx.doi.org/10.4049/jimmunol.0901737 | DOI Listing |
Sci Rep
January 2025
Department of Veterinary Physiology, College of Veterinary Medicine, Gyeongsang National University, Gazwa, Jinju, 52828, Republic of Korea.
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by immune dysregulation and excessive cytokine production. This study aimed to explore the potential of Camellia sinensis L. water extract (CSE) as a treatment for AD by the impact of CSE on inflammatory responses in keratinocytes, particularly concerning the production of inflammatory cytokines and the modulation of signaling pathways relevant to AD pathogenesis.
View Article and Find Full Text PDFMetabolism
January 2025
Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA, USA. Electronic address:
Introduction: Type 1 diabetic human islet β-cells are deficient in double C 2 like domain beta (DOC2b) protein. Further, DOC2b protects against cytokine-induced pancreatic islet β-cell stress and apoptosis. However, the mechanisms underpinning the protective effects of DOC2b remain unknown.
View Article and Find Full Text PDFIntroduction: Type 1 diabetic human islet β-cells are deficient in double C 2 like domain beta (DOC2b) protein. Further, DOC2b protects against cytokine-induced pancreatic islet β-cell stress and apoptosis. However, the mechanisms underpinning the protective effects of DOC2b remain unknown.
View Article and Find Full Text PDFPharmaceuticals (Basel)
October 2024
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea.
Background: This study aims to explore the protective role of JB-V-60-a novel synthetic derivative of decur-sin-against lipopolysaccharide (LPS)-induced inflammation.
Methods: We examined the effects of JB-V-60 on heme oxygenase (HO)-1, cyclooxygenase (COX)-2, and inducible nitric oxide synthase (iNOS) in LPS-activated human pulmonary artery endothelial cells (HPAECs). Additionally, we assessed its effects on iNOS, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β in LPS-exposed mice.
Int J Mol Sci
September 2024
Bacteriology Laboratory, Butantan Institute, São Paulo 05585-000, Brazil.
Several natural products are being studied to identify new bioactive molecules with therapeutic potential for infections, immune modulation, and other pathologies. TLRs are a family of receptors that play a crucial role in the immune system, constituting the first line of immune defense. They recognize specific products derived from microorganisms that activate multiple pathways and transcription factors in target cells, which are vital for producing immune mediators.
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