Open AccessCaspase 1–independent activation of interleukin‐1β in neutrophil‐predominant inflammation
Author(s) -
Guma Monica,
Ronacher Lisa,
LiuBryan Ru,
Takai Shinji,
Karin Michael,
Corr Maripat
Publication year - 2009
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.24959
Subject(s) - chymase , elastase , chemistry , arthritis , caspase 1 , proteases , immunology , pharmacology , inflammation , medicine , inflammasome , biochemistry , enzyme
Objective Interleukin‐1β (IL‐1β) is a key cytokine linked to the pathogenesis of acute arthritis. Caspase 1, neutrophil elastase, and chymase all process proIL‐1β to its biologically active form. This study was undertaken to examine the potential contributions of each of these proteases in experimental models of inflammatory arthritis. Methods Caspase 1–deficient ( Casp1 −/− ) and wild‐type (WT) mice were tested for their response to arthritogenic K/BxN serum transfer for induction of arthritis or injection of monosodium urate monohydrate (MSU) crystals for induction of peritonitis. All mice were prophylactically treated with inhibitors of neutrophil elastase or chymase. Arthritic paws were tested for the presence of IL‐1β protein by enzyme‐linked immunosorbent assay and Western blotting. Neutrophils and mast cells from WT and mutant mice were tested for their ability to secrete IL‐1β after in vitro stimulation, in the presence of protease inhibitors. Results Casp1 −/− and WT mice developed paw swelling to the same extent in the K/BxN serum transfer–induced arthritis model. MSU crystal injection into Casp1 −/− mice also resulted in neutrophil influx and production of measurable peritoneal IL‐1β protein. Both of these responses were attenuated with neutrophil elastase inhibitors. K/BxN serum transfer–induced arthritis was also reduced by treatment with a chymase inhibitor. Casp1 −/− neutrophils and mast cells, when exposed to MSU crystals, secreted similar amounts of IL‐1β protein upon in vitro stimulation with lipopolysaccharide, albeit at lower levels than that secreted by WT cells. Elastase and chymase inhibitors reduced the amount of IL‐1β released by these cells. Conclusion The production of IL‐1β by neutrophils and mast cells is not exclusively dependent on caspase 1, and other proteases can compensate for the loss of caspase 1 in vivo. These pathways might therefore compromise the caspase 1–targeted therapies in neutrophil‐predominant arthritis.