positive regulation of interleukin-18-mediated signaling pathway

Definition

Target type: biologicalprocess

Any process that activates or increases the frequency, rate or extent of interleukin-18-mediated signaling pathway. [GOC:obol]

Positive regulation of interleukin-18 (IL-18)-mediated signaling pathway is a crucial biological process involved in the activation and modulation of immune responses. IL-18, a pro-inflammatory cytokine, plays a critical role in the initiation and amplification of inflammatory cascades, primarily by inducing the production of interferon-gamma (IFN-γ) and other pro-inflammatory mediators.

The positive regulation of IL-18-mediated signaling pathway involves a complex interplay of signaling molecules and cellular events. It begins with the binding of IL-18 to its receptor, IL-18Rα, expressed on the surface of immune cells, such as T lymphocytes, natural killer (NK) cells, and macrophages. This binding event triggers the recruitment of the IL-18Rβ subunit, forming a heterodimer complex that initiates downstream signaling cascades.

The activated IL-18R complex recruits adaptor proteins, such as MyD88 and TRAF6, which in turn activate downstream signaling pathways, including the NF-κB pathway and the MAPK pathway. NF-κB activation leads to the transcription of pro-inflammatory genes, including TNF-α, IL-1β, and IL-6, while MAPK activation promotes the production of chemokines and other inflammatory mediators.

The IL-18 signaling pathway also involves the activation of the caspase-1 enzyme, which processes the precursor form of IL-18 into its active mature form. Mature IL-18 is then secreted from cells, further amplifying the inflammatory response.

Positive regulation of IL-18 signaling can be influenced by various factors, including:

- **Inflammation:** Inflammatory stimuli, such as bacterial or viral infections, can induce the expression of IL-18 and its receptor, enhancing the sensitivity of cells to IL-18.
- **Cytokines:** Other pro-inflammatory cytokines, such as TNF-α and IL-1β, can synergistically enhance IL-18-mediated signaling.
- **Toll-like receptor (TLR) activation:** TLRs recognize pathogen-associated molecular patterns (PAMPs), leading to the activation of signaling pathways that upregulate IL-18 production.
- **Microbiota:** The composition of the gut microbiota can influence IL-18 production and signaling.
- **Genetic factors:** Polymorphisms in IL-18 and IL-18R genes can affect the responsiveness to IL-18.

The positive regulation of IL-18-mediated signaling pathway is essential for mounting appropriate immune responses against pathogens and for maintaining tissue homeostasis. However, dysregulation of this pathway can contribute to the development of chronic inflammatory diseases, such as inflammatory bowel disease, rheumatoid arthritis, and sepsis.
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