RESEARCH - Kallikreins, kininogens and kinin receptors on circulating and synovial fluid neutrophils: role in kinin generation in RA

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Rheumatology Advance Access published online on March 1, 2009

Rheumatology, doi:10.1093/rheumatology/kep016

Kallikreins, kininogens and kinin receptors on circulating and

synovial fluid neutrophils: role in kinin generation in rheumatoid

arthritis

Bilkish Cassim1, Odette M. Shaw2, Margaret Mazur3, Neil L. Misso2,

Anupam Naran4, Langlands3, Philip J. 2 and Kanti D.

Bhoola2,5

1Department of Geriatrics, 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

Gairdner Hospital, 4PathWest, Queen II Medical

Centre, Perth, Australia and 5Department of Clinical and Experimental

Pharmacology, Mandela School of Medicine, University of Natal,

Durban, South Africa

Abstract

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.

http://rheumatology.oxfordjournals.org/cgi/content/abstract/kep016v1?papetoc

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