Expression and alternative processing of IL-18 in human 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-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.
Robertson
Susan E
SE
CRD, Division of Immunology, Infection & Inflammation, Glasgow Royal Infirmary, Glasgow, UK.
Young
John D
JD
Kitson
Susan
S
Pitt
Andrew
A
Evans
Jamie
J
Roes
Jurgen
J
Karaoglu
Denise
D
Santora
Ling
L
Ghayur
Tariq
T
Liew
Foo Y
FY
Gracie
J Alastair
JA
McInnes
Iain B
IB
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*
D020382:Interleukin-18; D007371:Interferon-gamma; D010447:Peptide Hydrolases