Kallikreins, kininogens and kinin receptors on circulating and synovial fluid neutrophils: role in kinin generation in rheumatoid arthritis.
OBJECTIVE
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 B(1) and B(2) 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.
Cassim
Bilkish
B
Department of Geriatrics, Nelson Mandela School of Medicine, University of Natal, Durban, South Africa.
Shaw
Odette M
OM
Mazur
Margaret
M
Misso
Neil L
NL
Naran
Anupam
A
Langlands
Daniel R
DR
Thompson
Philip J
PJ
Bhoola
Kanti D
KD
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D006801:Humans; D016234:Kallikrein-Kinin System / Q000502:physiology*; D007610:Kallikreins / Q000378:metabolism; D007704:Kininogens / Q000378:metabolism; D007705:Kinins / Q000096:biosynthesis; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism*; D043783:Receptor, Bradykinin B1 / Q000378:metabolism; D043782:Receptor, Bradykinin B2 / Q000378:metabolism; D013582:Synovial Fluid / Q000378:metabolism*; D055815:Young Adult
D007704:Kininogens; D007705:Kinins; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D007610:Kallikreins