Institute for Quantitative and Computational Biosciences and Department for Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA, USA.
Department of Medicine, Division of Infectious Diseases, David Geffen School of Medicine and Department for Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA, USA.
EMBO Rep. 2023 Jul 5;24(7):e55986. doi: 10.15252/embr.202255986. Epub 2023 May 22.
Tumor necrosis factor (TNF) is a key inflammatory cytokine that warns recipient cells of a nearby infection or tissue damage. Acute exposure to TNF activates characteristic oscillatory dynamics of the transcription factor NFκB and induces a characteristic gene expression program; these are distinct from the responses of cells directly exposed to pathogen-associated molecular patterns (PAMPs). Here, we report that tonic TNF exposure is critical for safeguarding TNF's specific functions. In the absence of tonic TNF conditioning, acute exposure to TNF causes (i) NFκB signaling dynamics that are less oscillatory and more like PAMP-responsive NFκB dynamics, (ii) immune gene expression that is more similar to the Pam3CSK4 response program, and (iii) broader epigenomic reprogramming that is characteristic of PAMP-responsive changes. We show that the absence of tonic TNF signaling effects subtle changes to TNF receptor availability and dynamics such that enhanced pathway activity results in non-oscillatory NFκB. Our results reveal tonic TNF as a key tissue determinant of the specific cellular responses to acute paracrine TNF exposure, and their distinction from responses to direct exposure to PAMPs.
肿瘤坏死因子 (TNF) 是一种关键的炎症细胞因子，它警告临近的感染或组织损伤的受体细胞。急性暴露于 TNF 会激活转录因子 NFκB 的特征性振荡动力学，并诱导特征性的基因表达程序；这些与直接暴露于病原体相关分子模式 (PAMPs) 的细胞的反应不同。在这里，我们报告称，持续的 TNF 暴露对于保护 TNF 的特定功能至关重要。在没有持续 TNF 调节的情况下，急性暴露于 TNF 会导致 (i) NFκB 信号转导的动态性不那么振荡，更类似于 PAMP 响应性 NFκB 动力学，(ii) 免疫基因表达更类似于 Pam3CSK4 反应程序，以及 (iii) 更类似于 PAMP 响应性变化的广泛表观遗传重编程。我们表明，缺乏持续的 TNF 信号会对 TNF 受体的可用性和动力学产生微妙的影响，从而增强途径活性导致非振荡性 NFκB。我们的结果揭示了持续的 TNF 作为急性旁分泌 TNF 暴露对特定细胞反应的关键组织决定因素，以及它们与直接暴露于 PAMPs 的反应的区别。
