title: Expression and alternative processing of IL-18 in human 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 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-gamma-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.
authors.affiliation: CRD, Division of Immunology, Infection & Inflammation, Glasgow Royal Infirmary, Glasgow, UK.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Robertson
authors.forename: John D
authors.initials: JD
authors.lastname: Young
authors.forename: Susan
authors.initials: S
authors.lastname: Kitson
authors.forename: Andrew
authors.initials: A
authors.lastname: Pitt
authors.forename: Jamie
authors.initials: J
authors.lastname: Evans
authors.forename: Jurgen
authors.initials: J
authors.lastname: Roes
authors.forename: Denise
authors.initials: D
authors.lastname: Karaoglu
authors.forename: Ling
authors.initials: L
authors.lastname: Santora
authors.forename: Tariq
authors.initials: T
authors.lastname: Ghayur
authors.forename: Foo Y
authors.initials: FY
authors.lastname: Liew
authors.forename: J Alastair
authors.initials: JA
authors.lastname: Gracie
authors.forename: Iain B
authors.initials: IB
authors.lastname: McInnes
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D020382:Interleukin-18 / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D018375:Neutrophil Activation / Q000235:genetics / Q000276:immunology*; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology*; D010447:Peptide Hydrolases / Q000172:deficiency / Q000276:immunology; D011499:Protein Processing, Post-Translational / Q000276:immunology*; D022142:Secretory Vesicles / Q000201:enzymology / Q000276:immunology*
chemical_list: D020382:Interleukin-18; D007371:Interferon-gamma; D010447:Peptide Hydrolases