utocrine role of endogenous interleukin‐18 on inflammatory cytokine generation by human neutrophils

Abstract

Neutrophils are key players of innate immunity and influence inflammatory and immune reactions through the production of numerous cytokines. Interleukin-18 (IL-18) is known to stimulate several neutrophil responses, and recent evidence suggests that neutrophils might represent a source of IL-18. Here, we show that neutrophils constitutively produce both IL-18 and its antagonist, IL-18BP. Cell activation does not affect IL-18BP release but leads to an increased gene expression and secretion of IL-18, a process that depends on NF-kappaB activation. Moreover, endogenous IL-18 feeds back on the neutrophils to augment cytokine generation in lipopolysaccharide-treated cells. Accordingly, exogenous IL-18 can induce the gene expression and release of several inflammatory cytokines in neutrophils, including its own expression. We finally report that IL-18 activates the p38 MAPK, MEK/ERK, and PI3K/Akt pathways in neutrophils. The IKK cascade is also activated by IL-18, resulting in IkappaB-alpha degradation, NF-kappaB activation, and RelA phosphorylation. Accordingly, these pathways contribute to the generation of inflammatory cytokines in IL-18-stimulated neutrophils. By contrast, the phosphorylation and DNA-binding activity of various STAT proteins were not induced by IL-18. Collectively, our results unveil new interactions between IL-18 and neutrophils and further support a role for these cells in influencing both innate and adaptive immunity.

Interleukin-18 Delays Neutrophil Apoptosis following Alcohol Intoxication and Burn Injury

“…In the present study, we observed a decrease in caspase-3 activity in neutrophils after the combined insult of EtOH and burn injury, and normalization of the caspase-3 activity following the administration of anti-IL-18 antibody. IL-18 has been shown to activate the p38 MAPK pathway in neutrophils (24,40). IL-18 activated p38 MAPK in a Ca 2+ -dependent manner that was directly influenced by the IL-18 concentration and the incubation time (40).…”

“…Apart from activating the p38 MAPK pathway, IL-18 has also been shown to activate the phosphatidylinositol-3 kinase (PI3K)/Akt pathway (24). PI3K is another key signal transducer for neutrophil survival (43,44).…”

“…In the presence of IL-1β-converting enzyme (ICE, or caspase-1), the precursor protein matures into an 18-kDa active protein (22), which is produced by macrophages, dendritic cells, neutrophils and epithelial cells (22,23). Neutrophils constitutively produce both IL-18 and its antagonist, IL-18 BP (24). Neutrophils were also found to constitutively express IL-18 receptors (α and β) (25), and thus an increase in IL-18 levels following EtOH and burn injury may modulate neutrophil effector functions, including their survival.…”

Human Conjunctival Transcriptome Analysis Reveals the Prominence of Innate Defense inChlamydia trachomatisInfection

“…It is also well recognized that T cell-derived IL-2 can activate NK cells, and recent evidence suggests that Ag-specific IL-2 from effector memory T cells can in effect immediately "recall" NK cells which degranulate and secrete IFN-␥ (35,36). Thus, in the presence of IL-2, IL-12, and IL-18, the local inflammatory responses are directed toward strong type I and IFN-␥ responses (1,26,73). Therefore, the strong expression signature of NK cells observed in these conjunctival samples, which reflects those seen after several natural ocular challenge infections or episodes of disease, could be explained by the boosting effect of antigen-specific effector memory T cells.…”

Discovery and Validation of Immunological Biomarkers in Milk for Health Monitoring of Dairy Cows - Results from a Multiomics Approach

“…During inflammation VEGF serves as chemoattractant for monocytes and macrophages and stimulates angiogenesis [65,66]. Activated PMN are further able to produce S100A9 and IL-18 [67][68][69], what could explain the elevated mRNA expression and higher protein concentration of these factors detected in MC and milk during disease. IL-18 and S100 proteins are known as mediators of the inflammatory neutrophil response in humans [70][71][72].…”