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Activation of NALP 1 inflammasomes in rats with adjuvant arthritis; a novel therapeutic target of carboxyamidotriazole in a model of rheumatoid arthritis
Author(s) -
Zhu Lei,
Li Juan,
Guo Lei,
Yu Xiaoli,
Wu Danwei,
Luo Lifeng,
Zhu Lingzhi,
Chen Wei,
Chen Chen,
Ye Caiying,
Zhang Dechang
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13138
Subject(s) - rheumatoid arthritis , arthritis , medicine , proinflammatory cytokine , nalp3 , inflammation , adjuvant , immunology , cancer research , chemistry , inflammasome
Background and Purpose Pro‐inflammatory cytokines are important in rheumatoid arthritis ( RA ) and their production is mainly regulated by NF ‐ κB and inflammasomes. Carboxyamidotriazole ( CAI ) exhibits potent anti‐inflammatory activities by decreasing cytokines. Here, we have investigated NACHT , LRR and PYD domains‐containing protein ( NALP ) inflammasomes in a rat model of RA and explored the therapeutic effects of CAI in this model and the involvement of NF ‐ κB and inflammasomes in the actions of CAI . Experimental Approach The anti‐arthritic effects of CAI were assessed in the adjuvant arthritis ( AA ) model in rats, using radiological and histological techniques. NALP1 and NALP3 inflammasomes, NF ‐ κB pathway and pro‐inflammatory cytokines levels were measured with Western blots, immunohistochemistry and ELISA . Key Results CAI decreased the arthritis index, improved radiological and histological changes, and reduced synovial IL ‐1 β , IL ‐6, IL ‐18 and TNF ‐ α levels in rats with AA . Compared with normal rats, the 70 kDa NALP1 isoform was up‐regulated, NALP3 was down‐regulated, and levels of the 165 kDa NALP1 isoform and the adaptor protein ASC were unchanged in synovial tissue from AA rats. CAI reduced the 70 kDa NALP1 isoform and restored NALP3 levels in AA rats; CAI inhibited caspase‐1 activation in AA synovial tissue, but not its enzymic activity in vitro . In addition, CAI reduced expression of p65 NF ‐ κB subunit and IκBα phosphorylation and degradation in AA rats. Conclusion and Implications NALP1 inflammasomes were activated in synovial tissues from AA rats and appeared to be a novel therapeutic target for RA . CAI could have therapeutic value in RA by inhibiting activation of NF ‐ κB and NALP1 inflammasomes and by decreasing pro‐inflammatory cytokines.