Pre-Ligand Assembly Domain (PLAD) is an important therapeutic target in inflammatory arthritis (131.21)

Abstract Tumor necrosis factor (TNF)-α is an important proinflammatory cytokine and plays a crucial role in pathogenesis of inflammatory arthritis such as rheumatoid and septic arthritis. TNF-α exerts its effect by binding to the extracellular domain of TNF receptor (TNFR) 1 and 2. The amino-terminal portion of the TNFR extracellular domain, known as cysteine rich domain 1 (CRD1), or the pre-ligand binding assembly domain (PLAD), plays an important role in the TNFR signaling pathway. Our studies demonstrate that soluble TNFR1 and TNFR2 PLAD proteins could block the actions of TNF-α, the TNFR1 PLAD protein could significantly inhibit inflammatory arthritis such as arthritis induced by TNF-α, bacterial DNA, lipopolysaccharide and collagen. The TNFR1 PLAD protein could inhibit nuclear factor (NF)-κB activation and osteoclastogenesis triggered by TNF-α. The TNFR1 PLAD protein also could suppress expression of receptor activator of NF-κB (RANK), RANK ligand and TNFR1 in arthritic joints. To understand the mechanism of the PLAD protein inhibited inflammatory arthritis, we further studied how TNFR PLAD protein blocks the effect of TNF-α and inflammatory arthritis. Our data demonstrate that the TNFR PLAD may directly bind to TNFR and block relationship of TNF-α binding to TNFR. The TNFR1 PLAD protein could suppress the expression of matrix metalloproteinase and inducible nitric oxide synthase in collagen-induced arthritis. Our research findings indicate the TNFR1 PLAD protein may offer a new approach to inhibit the pathogenic effects of TNF-α, and may be a good prototype for a new generation of pharmaceuticals against TNFRs that could be useful in treatment of inflammatory arthritis.