negative regulation of tumor necrosis factor-mediated signaling pathway

Definition

Target type: biologicalprocess

Any process that decreases the rate or extent of the tumor necrosis factor-mediated signaling pathway. The tumor necrosis factor-mediated signaling pathway is the series of molecular signals generated as a consequence of tumor necrosis factor binding to a cell surface receptor. [GOC:dph, GOC:tb]

Negative regulation of tumor necrosis factor (TNF)-mediated signaling pathway is a critical cellular process that dampens the inflammatory and cytotoxic responses elicited by TNF. TNF is a pro-inflammatory cytokine that plays a central role in immune responses and host defense. However, excessive TNF signaling can contribute to the pathogenesis of various inflammatory and autoimmune diseases. To prevent detrimental consequences of overactive TNF signaling, cells have evolved intricate mechanisms to tightly regulate this pathway. These mechanisms involve a cascade of molecular interactions, including the activation of inhibitory receptors, the recruitment of adaptor proteins, and the activation of downstream signaling cascades.

The TNF signaling pathway begins with the binding of TNF to its receptor, TNFR1 (TNF receptor 1). Upon ligand binding, TNFR1 undergoes a conformational change that triggers the recruitment of adaptor proteins, such as TRADD (TNF receptor-associated death domain). TRADD then recruits other adaptor proteins, including TRAF2 (TNF receptor-associated factor 2) and RIP1 (receptor-interacting protein kinase 1), to form a signaling complex. This complex can activate two distinct signaling pathways: the NF-κB pathway and the apoptotic pathway.

The NF-κB pathway is crucial for the production of pro-inflammatory cytokines and the expression of genes involved in cell survival. Activation of the NF-κB pathway requires the phosphorylation and degradation of IκBα (inhibitor of NF-κB alpha), a protein that sequesters NF-κB in the cytoplasm. Once IκBα is degraded, NF-κB translocates to the nucleus, where it binds to DNA and activates gene expression.

The apoptotic pathway, on the other hand, leads to programmed cell death. This pathway is activated by the formation of the death-inducing signaling complex (DISC), which is composed of TRADD, FADD (Fas-associated death domain), and caspase-8. Caspase-8 is a protease that initiates the caspase cascade, ultimately leading to the execution of apoptosis.

Negative regulation of TNF signaling is essential to maintain cellular homeostasis and prevent excessive inflammation and tissue damage. Cells employ several strategies to dampen TNF signaling, including:

- **Inhibitory receptors:** TNFSF14 (LIGHT), TNFRSF14 (HVEM), and GITR (glucocorticoid-induced TNF receptor family-related gene) are inhibitory receptors that can bind to TNF and prevent its activation of TNFR1.
- **Adaptor protein competition:** Adaptor proteins like cIAP1 (cellular inhibitor of apoptosis protein 1) and cIAP2 can compete with TRADD for binding to TNFR1, preventing the formation of the signaling complex.
- **Deubiquitinases:** Deubiquitinases like A20 (TNFAIP3) and CYLD can remove ubiquitin tags from signaling proteins, inhibiting their activity and reducing TNF signaling.
- **Signaling pathway inhibitors:** Proteins like A20 and CYLD can also directly inhibit the activity of kinases involved in TNF signaling, such as RIP1 and IKK (IκB kinase).
- **Anti-inflammatory cytokines:** Cytokines like IL-10 (interleukin-10) and TGF-β (transforming growth factor beta) can suppress TNF production and signaling.

These regulatory mechanisms work in concert to ensure that TNF signaling is tightly controlled, preventing excessive inflammation and maintaining immune homeostasis. Disruptions in these regulatory processes can lead to various inflammatory and autoimmune diseases, highlighting the importance of negative regulation of TNF-mediated signaling pathway in health and disease.'
"

Proteins (7)

Compounds (101)