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Plasma kininogen and bradykinin receptors are required for collagen antibody‐induced arthritis (CAIA)
Author(s) -
yang aizhen,
Xie Zhanli,
Zhu Xuemei,
Wu Yi
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.656.7
Subject(s) - kininogen , kinin , arthritis , bradykinin , high molecular weight kininogen , chemistry , endocrinology , pathogenesis , medicine , receptor , proinflammatory cytokine , knockout mouse , inflammation , immunology , microbiology and biotechnology , biology
Studies in experimental and clinical arthritis have suggested that plasma kallikrein‐kinin system (KKS) plays an important role in the pathogenesis of arthritis, however, the elucidation of the underlying mechanisms awaits further investigation in gene deficient mouse model. High molecular weight kininogen (HK) is a major component of KKS, the activation of which induces HK cleavage to generate bradykinin (BK) and active form of HK (HKa). BK and HKa are both proinflammatory. In this study, we used a kininogen‐1 −/− (Kng1 −/− ) mouse strain we newly generated and double BK receptors knockout (B 2 RB 1 R −/− ) mice. In mice Kng1 gene drives the production of HK in plasma. Removals of Kng1 gene and plasma HK protein of Kng1 −/− mice were confirmed by RT‐PCR and Western‐blotting, respectively. To induce CAIA, three groups of mice (WT, Kng1 −/− , and B 2 RB 1 R −/− ) were injected intraperitoneally with anti‐type II collagen antibody cocktail (3 mg) on day 0 and LPS (50 μg) on day 3. WT mice started to develop joint swelling and erythema on day 5, and the increase in ankle joint diameter became marked on day 6 (1.32±0.13 mm) and peaked on day 8 (1.41±0.17 mm). In contrast, either Kng1 −/− or B 2 RB 1 R −/− mice did not develop joint arthritis ( p <0.01). Our results for the first time demonstrate an essential role of plasma HK in the pathogenesis of arthritis, and BK is a key mediator. Blockade of HK cleavage could be an attractive anti‐arthritic treatment.