Anti-Inflammatory Effects of Recombinant Human PDCD5 (rhPDCD5) in a Rat Collagen-Induced Model of Arthritis
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Anti-Inflammatory Effects of Recombinant Human PDCD5 (rhPDCD5) in a Rat Collagen-Induced Model of Arthritis Juan Xiao,1,2 Ge Li,1,2 Jia Hu,1,2 Liujing Qu,1,2 Dalong Ma,1,2 and Yingyu Chen1,2,3
Abstract—Programmed cell death 5 (PDCD5) was first identified as a gene upregulated in cells undergoing apoptosis. We recently demonstrated the inhibitory effect of PDCD5 on experimentally induced autoimmune encephalomyelitis. In this study, we investigated the anti-inflammatory effects of recombinant human PDCD5 (rhPDCD5) in a rat collagen-induced arthritis (CIA) model. We find that vaccination of collagen II (CII) induced CIA rats with rhPDCD5 significantly delayed the occurrence and reduced the severity of CIA rats. rhPDCD5 also restored the loss of Foxp3+ regulatory T (Treg) cells and decreased the population of Th1 and Th17 in CIA rats. Simultaneously, rhPDCD5 treatment suppressed the production of pro-inflammatory cytokines (interleukin (IL)-6, IL-17A, tumor necrosis factor-α (TNF-α), and interferon gamma (IFN-γ)) and increased the secretion of anti-inflammatory cytokines (transforming growth factor beta 1 (TGF-β1) and IL-10) in CIA rats. In addition, rhPDCD5 inhibited the ability of CII to induce proliferation of splenocytes and lymph node cells (LNCs) and promoted the CII-activated CD4+ cell apoptosis. These results of rhPDCD5-treated CIA rats were similar with those of recombinant human TNF-α receptor IgG Fc (rhTNFR:Fc). Thus, to our knowledge, we provide the first evidence that rhPDCD5 may be an efficient approach to diminishing exacerbated immune responses in CIA, indicating its therapeutic potential in the treatment of rheumatoid arthritis and other autoimmune diseases. KEY WORDS: PDCD5; regulatory T cells; collagen-induced arthritis; Th17; Th1.
CD4+CD25+Foxp3+ regulatory T (Treg) cells also play a critical role in autoimmune diseases, including RA [2]. Their numbers and activation status are associated with RA activity in general. Thus, therapeutic strategies targeting RA should consider the upregulation of Treg cell differentiation, as well as the inhibition of proinflammatory cells and pro-inflammatory cytokines. Programmed cell death 5 (PDCD5) was first identified as an apoptosis-promoting protein [3]. The decreased expression of PDCD5 has been detected in many human tumors, and restoration of PDCD5 with recombinant protein can significantly sensitize different cancer cells to chemotherapies [4–7]. Recombinant human PDCD5 (rhPDCD5) has been shown to enter a variety of cells by clathrin-independent endocytosis and exert biological activities [7]. Studies on molecular mechanism of PDCD5 have been proposed that PDCD5 interacts with the histone acetyltransferase Tip60 and the transcription factor p53 to promote apoptosis [8–10]. PDCD5 can also interact with other molecules such as NF-κB p65 [11] and CCT [12], in which participate in the regulation of cell apoptosis.
INTRODUCTION Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disease, characterized by inflammatory cell infiltration in the synovia
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