Autocrine role of endogenous interleukin-18 on inflammatory cytokine generation by human neutrophils.
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.
Fortin
Carl F
CF
Pulmonary Division, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, QC, Canada J1H 5N4.
Ear
Thornin
T
McDonald
Patrick P
PP
D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D016328:NF-kappa B; C118370:interleukin-18 binding protein; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D051550:I-kappa B Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases