negative regulation of tumor necrosis factor production

Definition

Target type: biologicalprocess

Any process that stops, prevents, or reduces the frequency, rate, or extent of tumor necrosis factor production. [GOC:mah, PMID:10891884, PMID:15560120]

Negative regulation of tumor necrosis factor (TNF) production is a complex process involving multiple cellular mechanisms that restrict the production and release of TNF, a potent pro-inflammatory cytokine. TNF plays a critical role in the immune response, but its excessive production can contribute to inflammation-mediated diseases like rheumatoid arthritis, inflammatory bowel disease, and sepsis. Therefore, tightly controlling TNF production is crucial for maintaining immune homeostasis and preventing pathology.

**Key Mechanisms of Negative Regulation:**

* **Transcriptional Regulation:**
* **NF-κB Inhibition:** TNF production is primarily driven by the transcription factor NF-κB. Several mechanisms inhibit NF-κB activation, including:
* **IκB Kinase (IKK) Inhibition:** IKKs are critical kinases that phosphorylate IκB, leading to its degradation and NF-κB activation. IKK inhibitors block this process, preventing NF-κB translocation to the nucleus.
* **A20 Induction:** A20 is a ubiquitin ligase that inhibits NF-κB signaling by targeting proteins involved in the NF-κB pathway for degradation.
* **RelB Activation:** RelB is a transcription factor that can compete with NF-κB for binding to TNF promoter regions, reducing TNF transcription.
* **STATs and Interferons:** STATs (Signal Transducers and Activators of Transcription) can be activated by interferons (IFNs), leading to the production of proteins that suppress TNF production.

* **Post-Transcriptional Regulation:**
* **mRNA Stability:** TNF mRNA is subject to rapid degradation by microRNAs (miRNAs), which bind to specific sequences in the mRNA and target it for degradation.
* **Translation Inhibition:** Proteins like tristetraprolin (TTP) bind to TNF mRNA and block its translation into protein.

* **Protein Processing and Secretion:**
* **TNF Precursor Processing:** TNF is produced as a precursor protein (pro-TNF). Its proteolytic cleavage by TNF-α converting enzyme (TACE) is required for its release. TACE inhibitors block this processing step, preventing TNF secretion.
* **TNF Receptor Binding:** TNF interacts with its receptors (TNFR1 and TNFR2). Binding to these receptors can trigger downstream signaling pathways that lead to negative feedback loops, reducing TNF production.

* **Immune Cell Modulation:**
* **Treg Cell Activity:** Regulatory T cells (Tregs) suppress the production of TNF by other immune cells, such as macrophages and T cells, through various mechanisms including the production of anti-inflammatory cytokines.
* **IL-10 Production:** Interleukin-10 (IL-10) is a potent anti-inflammatory cytokine that inhibits TNF production and promotes the resolution of inflammation.

**Key Players and Their Roles:**

* **TNF:** The primary target of negative regulation.
* **NF-κB:** Transcription factor that drives TNF production.
* **IKKs:** Kinases that activate NF-κB.
* **A20:** Ubiquitin ligase that inhibits NF-κB signaling.
* **RelB:** Transcription factor that competes with NF-κB.
* **STATs:** Transcription factors activated by IFNs.
* **miRNAs:** Small RNA molecules that degrade TNF mRNA.
* **TTP:** Protein that blocks TNF translation.
* **TACE:** Enzyme that processes pro-TNF.
* **TNFR1 and TNFR2:** TNF receptors involved in feedback inhibition.
* **Tregs:** Immune cells that suppress TNF production.
* **IL-10:** Anti-inflammatory cytokine that inhibits TNF.

**Conclusion:**

Negative regulation of TNF production is a complex and tightly controlled process involving multiple cellular mechanisms. These mechanisms ensure that TNF levels are maintained within a narrow range, preventing excessive inflammation and promoting immune homeostasis.'
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Proteins (20)

Compounds (520)