From the Guidelines
Elevated levels of Interleukin-1 beta (IL-1β) and Interleukin-18 (IL-18) can indicate activation of NLRP3 (Nucleotide-binding domain, leucine-rich repeat-containing family, pyrin domain-containing 3), as these cytokines are produced by inflammasome activation, which is a key component of the NLRP3 pathway 1.
Key Points
- IL-18 is a proinflammatory cytokine produced by inflammasome activation, which drives IFNγ overproduction 1.
- NLRP3 activation leads to the production of IL-1β and IL-18, which are key players in the inflammatory response 1.
- Elevated levels of IL-18 have been associated with macrophage activation syndrome (MAS), a life-threatening complication of systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD) 1.
- The measurement of IL-18 and other biomarkers, such as S100 proteins, can be useful in the diagnosis and management of sJIA and AOSD 1.
Biomarker Levels
- Elevated levels of IL-18 (>68,363 ng/mL) have been reported in patients with sJIA-MAS compared to those with active sJIA without MAS 1.
- IL-18 levels have also been shown to distinguish MAS from active sJIA with high sensitivity and specificity 1.
- The measurement of IL-18 and other biomarkers, such as CXCL9 and ADA2 activity, can be useful in the diagnosis and management of MAS 1.
From the Research
NLRP3 Inflammasome Activation
- Elevated levels of Interleukin-1 beta (IL-1β) and Interleukin-18 (IL-18) can indicate activation of NLRP3 inflammasome, as these cytokines are produced upon activation of the NLRP3 inflammasome 2, 3, 4.
- The NLRP3 inflammasome is a multiprotein complex that activates caspase-1, leading to the maturation of IL-1β and IL-18, and the induction of pyroptosis, a form of cell death 2.
- The activation of NLRP3 inflammasome can be triggered by diverse stimuli, including reactive oxygen species, lysosomal rupture, or cytosolic ion perturbation 5, 4.
IL-1β and IL-18 Production
- IL-1β and IL-18 have both shared and unique biological functions, with IL-1β being an important mediator of the acute phase response to infections and tissue damage, and IL-18 taking part in activation and tailoring of the adaptive immune response 3.
- The ratio of IL-1β to IL-18 production can vary depending on the stimulus used to activate the NLRP3 inflammasome, with some stimuli inducing a higher ratio of IL-1β to IL-18 production 3.
- The production of IL-1β and IL-18 is strictly dependent on a functional NLRP3 inflammasome, and the differences in their production do not depend on the level of gene expression, caspase-1 activity, or pyroptosis 3.
Regulation of NLRP3 Inflammasome
- The NLRP3 inflammasome is regulated by various metabolic pathways, which converge to modulate its activation 4.
- Micro-ribonucleic acid (RNA)-223 (miR-223) has been shown to regulate the NLRP3-inflammasome activation, and its expression is altered in patients with severe COVID-19 6.
- The dysregulation of NLRP3 inflammasome followed by IL-1β production has been implicated in the pathogenesis of various inflammatory diseases, including COVID-19 6.