negative regulation of interleukin-18 production

Definition

Target type: biologicalprocess

Any process that stops, prevents, or reduces the frequency, rate, or extent of interleukin-18 production. [GOC:mah, PMID:23710316]

Negative regulation of interleukin-18 (IL-18) production is a crucial process in controlling inflammation and immune responses. IL-18 is a pro-inflammatory cytokine that plays a vital role in promoting Th1 responses, NK cell activation, and the production of interferon-gamma (IFN-γ). Excessive IL-18 production can lead to chronic inflammation and autoimmune diseases. Therefore, tight regulation of its production is essential for maintaining immune homeostasis.

Several mechanisms contribute to the negative regulation of IL-18 production. One key pathway involves the inhibition of caspase-1 activation, the enzyme responsible for processing pro-IL-18 into its active form. Caspase-1 activation is tightly controlled by the inflammasome, a multiprotein complex that assembles in response to various stimuli, including pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). The NLRP3 inflammasome is the most well-characterized inflammasome involved in IL-18 production.

Several negative regulators can inhibit caspase-1 activation and IL-18 production. These include:

- **Inhibitors of NLRP3 inflammasome assembly:**
- **NLRP3 inhibitors:** Molecules that directly bind to NLRP3 and prevent its activation.
- **ASC inhibitors:** Inhibitors of the adaptor protein ASC, which is essential for inflammasome assembly.
- **Inhibitors of caspase-1 activation:**
- **Caspase-1 inhibitors:** Molecules that directly bind to caspase-1 and block its catalytic activity.
- **Caspase-1 antagonists:** Molecules that interfere with caspase-1 activation by competing with its substrates.

Another mechanism involves the inhibition of IL-18 expression at the transcriptional level. Several transcription factors, including NF-κB and AP-1, can activate IL-18 gene expression. Negative regulators can target these transcription factors to prevent their activation or promote their degradation.

Furthermore, post-translational modifications, such as ubiquitination and phosphorylation, can also modulate IL-18 production. Ubiquitination can target IL-18 for degradation, while phosphorylation can alter its activity or stability.

In addition to these intrinsic mechanisms, external factors, such as anti-inflammatory cytokines (e.g., IL-10) and immunosuppressive drugs, can also contribute to the negative regulation of IL-18 production. IL-10, for example, can suppress the expression of NLRP3 and other inflammasome components, leading to reduced IL-18 production.

In conclusion, the negative regulation of IL-18 production involves a complex interplay of different mechanisms, including the inhibition of caspase-1 activation, transcriptional regulation, post-translational modifications, and external factors. This intricate regulatory network ensures that IL-18 production is tightly controlled, preventing excessive inflammation and maintaining immune homeostasis.'
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Proteins (2)

Compounds (13)