IL‐18 Activity in Systemic Lupus Erythematosus

Abstract

Interleukin-18 (IL-18) is an inflammation-related cytokine that plays a central role both in innate defense reactions and in Th1 activation and specific immune responses. Increased levels of IL-18 can be detected in biological fluids and organs of individuals affected by several autoimmune pathologies, as well as in autoimmune animal models. In this review, the role of IL-18 in systemic lupus erythematosus (SLE) is critically examined, including its possible role in the pathogenesis of disease. In SLE, increased levels of IL-18 have been found in serum/plasma of affected persons, which positively correlated with disease severity. The possibility that circulating IL-18 levels are predictive of renal damage has been proposed, suggesting that IL-18 may be a prognostic marker of renal involvement useful to identify patients at risk of renal failure. The evaluation of urinary levels of free active IL-18 indeed suggests a correlation with the degree of renal involvement. The possible pathogenic role of IL-18 in lupus has been studied in a mouse model of progressive disease, which makes possible the identification, at the level of the different affected organs, of IL-18 changes preceding disease development and those appearing after disease onset. It can be concluded that IL-18 has a multifaceted role in autoimmune lupus, being apparently involved both in the effector phases of the late organ damage and, in some organs, in the initial pathogenic events. Therapeutic strategies targeting IL-18 in autoimmunity are under development.

Macrophage activation syndrome and cytokine-directed therapies

“…This is in distinct contrast to IL-18 levels in other diseases such as rheumatoid arthritis [82], sepsis [83], lupus erythematosus [84, 85], granulomatosis with polyangiitis [86], and chronic liver disease [79]. The most commonly used ELISA for circulating IL-18 detects about 100 pg/mL in the serum of healthy humans, whereas in diseases characterized by systemic inflammation, the levels rarely exceed 300 pg/mL.…”

NLRP3 and ASC suppress lupus-like autoimmunity by driving the immunosuppressive effects of TGF-β receptor signalling

“…Given its dominant proinflammatory role in innate immunity one would predict that the NLRP3 inflammasome will drive antigen-presentation, T cell priming, lymphocyte proliferation and finally, autoimmune tissue inflammation 29 30. Furthermore, nuclear lupus autoantigens and neutrophil extracellular traps potentially contribute to lupus activity by their NLRP3 agonistic effect 31–33.…”

Identification of a truncated splice variant of IL-18 receptor alpha in the human and rat, with evidence of wider evolutionary conservation

“…Studies have recently shown that U1 small nuclear RNA (snRNA), which is known for its role in splicing through recognition of 5′ splice sites, also plays a key role in suppressing the transcription of shorter transcripts associated with more 5′ polyadenylation signals, and thus regulates transcript length for genes with multiple polyadenylation signals (Kaida et al, 2010; Merkhofer & Johnson, 2012; Berg et al, 2012). Interestingly, autoantibodies to U1 snRNA occur in a number of autoimmune disorders (Breda et al, 2010; Kattah, Kattah & Utz, 2010), particularly mixed connective tissue disease and systemic lupus erythematosus, diseases in which altered IL-18 activity or its downstream effector, interferon-gamma (IFN- γ ), have been observed (Bakri Hassan et al, 1998; Bodolay et al, 2002; Favilli et al, 2009). Berg et al (2012) showed that depletion of U1 snRNA through RNA knockdown results in shorter transcripts corresponding to more 5′ polyadenylation signals.…”