Tumor Necrosis Factor Receptor Pre-Ligand Assembly Domain is an Important Therapeutic Target in Inflammatory Arthritis

Abstract

Tumor necrosis factor (TNF)-alpha is an important proinflammatory cytokine and plays a crucial role in pathogenesis of inflammatory arthritis, such as rheumatoid and septic arthritis. TNFalpha 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. TNFR1 PLAD and TNFR2 PLAD proteins block the actions of TNFalpha by interfering with assembly of the receptor complex required for TNFalpha binding. The TNFR1 PLAD protein have been shown to significantly inhibit inflammatory arthritis, such as arthritis induced by TNFalpha, bacterial DNA, lipopolysaccharide, and collagen. The TNFR1 PLAD protein inhibit nuclear factor (NF)-kappaB activation and osteoclastogenesis triggered by TNFalpha was able to inhibit expression of receptor activator of NF-kappaB (RANK), RANK ligand, matrix metalloproteinase and inducible nitric oxide synthase in collagen-induced arthritis. The TNFR1 PLAD protein could therefore be useful in treatment of inflammatory arthritis.