Death by TNF: a road to inflammation

Abstract

Tumour necrosis factor (TNF) is a central cytokine in inflammatory reactions, and biologics that neutralize TNF are among the most successful drugs for the treatment of chronic inflammatory and autoimmune pathologies. In recent years, it became clear that TNF drives inflammatory responses not only directly by inducing inflammatory gene expression but also indirectly by inducing cell death, instigating inflammatory immune reactions and disease development. Hence, inhibitors of cell death are being considered as a new therapy for TNF-dependent inflammatory diseases.

The TNFΔAREmouse as a model of intestinal fibrosis

“…While the genetic modification is mono-genetic, the subsequent increases in other pro-inflammatory as well as pro-fibrotic cytokines suggest that multiple pathways become involved, and this is also corroborated by the known complexity and incomplete understanding of TNF signaling. 34, 35…”

The Regulatory Axis of PD-L1 Isoform 2/TNF/T Cell Proliferation Is Required for the Canonical Immune-Suppressive Effects of PD-L1 Isoform 1 in Liver Cancer

“…It is well known that TNF induction is one of the earliest events in hepatitis, triggering a series of other cytokines that cooperate to recruit inflammatory cells, kill liver cells, and initiate a wound-healing response. TNF not only functions in liver inflammation, steatosis and fibrosis, but also plays oncogenic roles in liver cancer development, activating the proinflammatory transcription factor NF-κB to upregulate the expression of genes involved in tumor cell survival, proliferation, invasion, angiogenesis and metastasis [ 26 ]. Moreover, TNF is an important effector molecule targeting immunogenic tumor cells during tumor surveillance, which is critically required for effective priming, proliferation and recruitment of tumor-specific T cells [ 27 ].…”

A Synopsis of Current Theories on Drug-Induced Nephrotoxicity

“…Nephrotoxic agents, including cisplatin, activate phosphorylation and the subsequent translocation of NF-κB to the nucleus, finally leading to the increased transcription of specific genes encoding inflammatory mediators, including TNF-α. Thus, the increased expression of the cytokine in kidney tubular cells triggers their damage and death directly through TNF receptor type 1 (TNFR1) and indirectly by mounting a strong inflammatory response through TNF receptor type 2 (TNFR2) [ 83 , 84 , 85 ].…”