Roles of PADI4 in the expression of cytokines involved in inflammation and adhesion in differentiated NB4 cells treated with ATRA.

Differentiation syndrome (DS) is a common complication in patients with acute promyelocytic leukemia (APL) treated with all-trans-retinoic acid (ATRA). However, the target of ATRA during DS in patients with APL remains to be elucidated. Therefore, the current study aimed to investigate the role of peptidylarginine deiminase 4 (PADI4) in the differentiation of ATRA-induced NB4 APL cells. The results showed that PADI4 was significantly upregulated in peripheral blood samples derived from patients with APL DS compared with patients with APL only. In addition, whether ATRA could enhance the expression levels of PADI4 in NB4 cells was subsequently investigated. The results also showed that PADI4 overexpression promoted the differentiation of NB4 cells treated with ATRA, which was reversed after PADI4 silencing. To uncover the potential mechanisms underlying the above process, PADI4 overexpression induced the secretion of inflammation-related cytokines, such as TNF-α, IL-1β, IL-8, C-C motif chemokine (CCL)2, CCL4, CCR1 and intercellular adhesion molecule-1 in ATRA-treated NB4 cells. However, PADI4 knockdown in the same cells had the opposite effect. The above findings indicated that PADI4 could be involved in the differentiation of ATRA-induced NB4 cells and upregulation of cytokines.