Department of Biochemistry and Molecular Pharmacology
Biochemistry | Enzymes and Coenzymes | Immunity | Medicinal-Pharmaceutical Chemistry | Musculoskeletal Diseases
Proteins containing citrulline, a post-translational modification of arginine, are generated by peptidyl arginine deiminases (PAD). Citrullinated proteins have pro-inflammatory effects in both innate and adaptive immune responses. Here, we examine the therapeutic effects in collagen-induced arthritis of the second generation PAD inhibitor, BB-Cl-amidine. Treatment after disease onset resulted in the reversal of clinical and histological changes of arthritis, associated with a marked reduction in citrullinated proteins in lymph nodes. There was little overall change in antibodies to collagen or antibodies to citrullinated peptides, but a shift from pro-inflammatory Th1 and Th17-type responses to pro-resolution Th2-type responses was demonstrated by serum cytokines and antibody subtypes. In lymph node cells from the arthritic mice treated with BB-Cl-amidine, there was a decrease in total cell numbers but an increase in the proportion of Th2 cells. BB-Cl-amidine had a pro-apoptotic effect on all Th subsets in vitro with Th17 cells appearing to be the most sensitive. We suggest that these immunoregulatory effects of PAD inhibition in CIA are complex, but primarily mediated by transcriptional regulation. We suggest that targeting PADs is a promising strategy for the treatment of chronic inflammatory disease.
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Copyright © 2016, The Author(s).
DOI of Published Version
Sci Rep. 2016 May 23;6:26430. doi: 10.1038/srep26430. Link to article on publisher's site
Kawalkowska, Joanna; Quirke, Anne-Marie; Ghari, Fatemeh; Davis, Simon; Subramanian, Venkataraman; Thompson, Paul R.; Williams, Richard O.; Fischer, Roman; La Thangue, Nicholas B.; and Venables, Patrick J., "Abrogation of collagen-induced arthritis by a peptidyl arginine deiminase inhibitor is associated with modulation of T cell-mediated immune responses" (2016). Open Access Articles. 2834.
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