Expression and alternative processing of IL‐18 inhuman neutrophils

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 caspase‐independent 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‐γ‐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.