Polymorphism in the tumour necrosis factor receptor II gene is associated with circulating levels of soluble tumour necrosis factor receptors in rheumatoid arthritis

Tumour necrosis factor (TNF)-α is a pleiotropic cytokine that is important in the pathogenesis of rheumatoid arthritis (RA), in which it plays a role in cartilage degradation, bone resorption, adhesion molecule expression, leucocyte infiltration, enzyme production and cytokine synthesis (see reviews by Brennan and coworkers [1] and Choy and Panayi [2]). The actions of TNF-α are mediated through binding to two distinct cell surface receptors, namely tumour necrosis factor receptor I (TNF-RI) and II (TNF-RII) [3,4]. Both are transmembrane glycoproteins with a three domain structure: a multiple cysteine-rich motif bearing an extracellular domain that facilitates ligand binding; a hydrophobic membrane spanning domain; and an intracellular domain that mediates signal transduction. The receptor molecules share significant homology in their extracellular domains but they have distinct intracellular domains [5]. Most significantly, TNF-RI, but not TNF-RII, possesses a death domain that can transduce the signal for cell death [6]. The two receptors appear to promote distinct TNF-α-induced cellular responses, although both are capable of inducing the nuclear factor-κB (NF-κB) and apoptotic pathways [7-10], providing some evidence of receptor function redundancy.In addition to membrane bound forms, both TNF receptors can exist as soluble proteins. These are soluble variants of the extracellular domains [11-13] and are derived from the membrane bound form by the proteolytic actions of a disintegrin metalloproteinase called TNF-α converting enzyme (TACE) [14]. They retain their ligand binding capacity after cleavage [11,13] and can act as natural inhibitors of TNF-α by sequestering soluble TNF-α and preventing it from binding to membrane-bound TNF receptor. The levels of soluble TNF receptors (sTNFRs) are elevated in the serum and synovial fluid of RA patients [15-17], but these levels appear to be insufficient to prevent the chronic inflammation promoted by TNF-α [16]. Furtherm