Expression and alternative processing of IL‐18 inhuman neutrophils

Abstract

Interleukin-18 (IL-18), a member of the IL-1 cytokine superfamily, is an important regulator of both innate and acquired immune responses. We demonstrate here constitutive expression of IL-18 by human neutrophils. Unexpectedly, we observed that neutrophils from peripheral blood or rheumatoid synovial compartments contained not only pro and mature IL-18, but also several novel smaller-molecular-weight IL-18-derived species. Using specific protease inhibitors, and serine protease gene-targeted mice, we demonstrate that these IL-18-derived products arose through caspaseindependent cleavage events mediated by the serine proteases, elastase and cathepsin G. Moreover, we report that the net effect of elastase treatment of mature recombinant IL-18 was to reduce its IFN-c-inducing activity. Thus, human neutrophils contain IL-18 and IL-18-derived molecular species that can arise through novel enzymatic processing pathways. Through cytosolic, membrane or secretory expression of such processing enzymes, together with generation of IL-18 itself, neutrophils likely play a critical role in regulating IL-18 activities during early innate immune responses.

TLR-Stimulated Neutrophils Instruct NK Cells To Trigger Dendritic Cell Maturation and Promote Adaptive T Cell Responses

“…These experiments suggest that overnight cultures of TLR-stimulated PMNs may contain species of IL-18 that are not detected by the ELISA, which is in line with previous reports demonstrating that neutrophil-derived proteases generate low m.w. species of IL-18 (23). To address this issue, we exposed rIL-18 to the neutrophil enzyme, elastase.…”

Neutrophil serine proteases fine-tune the inflammatory response

“…However, stimulation of epithelial cells with IFN-γ in the presence of PR3 and lipopolysaccharide (LPS) leads to the release of biologically active mature IL-18, independent of caspase 1 (Sugawara et al, 2001). In contrast, it has been shown that mature IL-18 released by neutrophils can be proteolysed by NE leading to diminished biological activity (Robertson et al, 2006).…”

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

“…IL-18, a proinflammatory cytokine, belongs to the IL-1 cytokine superfamily and is synthesized as a precursor protein (pro-IL-18). 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).…”