Rheumatology Advance Access originally published online on March 1, 2009
Rheumatology 2009 48(5):490-496; doi:10.1093/rheumatology/kep016
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Kallikreins, kininogens and kinin receptors on circulating and synovial fluid neutrophils: role in kinin generation in rheumatoid arthritis
1Department of Geriatrics, Nelson Mandela School of Medicine, University of Natal, Durban, South Africa, 2Lung Institute of Western Australia, Centre for Asthma, Allergy and Respiratory Research, The University of Western Australia, 3Department of Rheumatology, Sir Charles Gairdner Hospital, 4PathWest, Queen Elizabeth II Medical Centre, Perth, Australia and 5Department of Clinical and Experimental Pharmacology, Nelson Mandela School of Medicine, University of Natal, Durban, South Africa.
Correspondence to: Kanti D. Bhoola, Lung Institute of Western Australia, Ground Floor, E Block, Sir Charles Gairdner Hospital, Nedlands, WA 6009, Australia. E-mail: profbhoola{at}iinet.net.au
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Abstract |
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Objectives. Neutrophils traffic into and have the capacity to generate kinins in SF of RA patients. The aim of this study was to assess the expression of kallikreins, kininogens and kinin receptors in circulating and SF neutrophils, as well as synovial tissue of RA patients, and to assess kinin generation in SF.
Methods. Neutrophils were isolated from blood and SF of RA patients and blood of healthy volunteers. Expression of kallikreins, kininogens and kinin receptors in neutrophils and synovial tissue was assessed by immunocytochemistry using specific antibodies, with visualization by brightfield and confocal microscopy. Levels of basal and generated kinins in SF of RA patients were measured by ELISA.
Results. Kinin labelling was significantly reduced, indicating the loss of the kinin moiety from kininogen on circulating (P < 0.001) and SF neutrophils (P < 0.05) of RA patients. Immunolabelling of tissue kallikrein was also decreased, whereas kinin B1 and B2 receptor expression was increased in circulating and SF neutrophils of RA patients. Immunolabelling of kallikreins and kinin receptor proteins was similar in RA and normal synovial tissues. The basal kinin level in SF of RA patients was 5.7 ± 6.1 ng/ml and the mean concentration of kinins generated in vitro was 80.6 ± 56.3 ng/ml. The capacity for kinin generation was positively correlated with measures of disease activity.
Conclusions. Kallikrein–kinin proteins on neutrophils play an important role in kinin generation and the pathophysiology of RA. Specific kallikrein and kinin receptor antagonists may be useful as IA therapies for inflamed joints.
KEY WORDS: RA, Neutrophils, Synovium, Kallikreins, Kinins, Kinin receptors, Kininogen, Tender and swollen joints
Submitted 26 August 2008;
revised version accepted 14 January 2009.
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