PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of arthresbiomed central web sitesearch.manuscript submission.see also journal with issn 1478-6354registration.reference to the article.journal front page.
 
Arthritis Res. 2001; 3(Suppl A): P020.
Published online Jan 26, 2001. doi:  10.1186/ar189
PMCID: PMC3273229
Human neutrophil production and cleavage of IL-18: potentiating inflammatory arthritis?
SE Robertson,1 J Young,1 FY Liew,1 IB McInnes,1 and JA Gracie1
1CRD/Department of Medicine, and Department of Immunology, Glasgow Royal Infirmary, Glasgow, G31 2ER, Scotland
Supplement
21st European Workshop for Rheumatology Research
Conference
21st European Workshop for Rheumatology Research
1-4 March 2001
Vienna, Austria
Received January 15, 2001
 
We have recently demonstrated the presence and involvement of IL-18 in rheumatoid arthritis (RA) synovitis. Moreover, blockade of IL-18 in vivo is protective in arthritis models. We sought to demonstrate for the first time the production and intracellular processing of IL-18 by human neutrophils. Thereafter we investigated novel processing pathways and potential regulatory mechanisms for IL-18 bioactivity that could operate in synovium.
Methods
Matched peripheral blood (PB) and synovial fluid (SF) neutrophils were isolated by ficoll density gradients. IL-18 was detected in neutrophil total protein lysates by western blotting. Serum free neutrophil culture supernatants were incubated with recombinant IL-18 prior to HPLC fractionation and assessed for biological activity using IL-18 sensitive KG-1 cells.
Results
Western blotting of neutrophil lysates isolated from PB and SF of rheumatoid and psoriatic arthritis patients demonstrated the presence of a number of IL-18 specific bands ranging in molecular weight from 22 to 6 kD in size, representing pro, mature and possible IL-18 cleavage products. HPLC purified culture supernatants from PB and SF neutrophils contain heat sensitive enzymatic activity capable of in vitro cleavage of both recombinant pro and mature IL-18. This caspase independent cleavage of IL-18 resulted in the generation of biologically active fragments capable of modulating IL-18 induced IFN-g production by KG-1 cells.
Conclusions
These data demonstrate for the first time that modified fractions of IL-18 may be biologically active, suggesting the existence of a novel regulatory mechanism in the IL-1 cytokine family. In light of their rapid accumulation in large numbers within RA joints, our data further suggest that both neutrophils and IL-18 play important roles in disease pathogenesis.
Articles from Arthritis Research are provided here courtesy of
BioMed Central