NSC1122002, a TRAF-binding domain inhibitor, inhibits collagen-induced arthritis in a mouse model

Dysregulation of IL-12 and IL-23 is related to many autoimmune diseases including arthritis. The production of IL-12 and IL-23 were reported to be under the control of JMJD2D, whose activity and stability were promoted by the TRAF-binding domain (TRABID), a deubiquitinating enzyme that epigenetically modulated inflammatory gene expression. NSC1122002 is a novel inhibitor of TRABID, and this study aimed to examine the effects of NSC1122002 on the expression of IL-12 and IL-23 both in vitro and in vivo in the context of collagen-induced arthritis, consequently to evaluate its potential as a drug candidate for treating inflammatory disease.Bone marrow cells were isolated to detect the effect of NSC1122002 on the development of innate immune cells and other precursor cells. Primary macrophages and osteoclasts were used to examine the impact of NSC1122002 on cytokine expression. Collagen-induced arthritis was established to determine the function of NSC1122002 in vivo.NSC112200 did not affect the development of innate immune cells, primary osteoclast, and haematopoietic stem cells. NSC112200 specifically downregulated the expression of IL-12 and IL-23 through promoting degradation of JMJD2D by directly inhibited the deubiquitinating activity of TRABID. Besides, NSC112200 significantly suppressed the induction of CIA in mice.Our findings provided new insight into the pathological mechanism and intervention method for arthritis therapy and identified that NSC112200 could be a potential drug for treating autoimmune diseases.