Targeting interleukin‐1 in the treatment of rheumatoid arthritis (2002)

Numerous observations support the suggestion that tissue destruction and resulting disability in rheumatoid arthritis (RA) are the result of extracellular matrix degradation by proteolytic enzymes, including matrix metalloproteinases and aggrecanases. These enzymes are induced by proinflammatory cytokines, predominantly interleukin-1 (IL-1). In vitro experiments and animal models have confirmed that a strong synergism exists between IL-1 and tumor necrosis factor (TNF ) with regard to many biologic functions (1). IL-1 and TNF are mainly produced by monocyte/macrophages which are activated by soluble factors and, more important, by direct contact with stimulated T cells at the inflammatory site. Each of the two cytokines can be induced by different, distinct stimuli and involve different kinetics. TNF is predominantly detected during the early stages of disease, more evidently at the systemic level. Both IL-1 and IL-1 are detected at all phases of RA and are abundant at the local level. This pattern of cytokine expression justifies the therapeutic use of IL1–blocking therapy at any stage of the disease. The mechanisms of IL-1, one of the key mediators of bone resorption and cartilage destruction in RA, may be controlled at several levels, some of which are independent of TNF . For instance, IL-1 production is strongly induced in monocyte/macrophages upon direct cellular contact with stimulated T lymphocytes, in the absence of TNF (2). This mechanism is blocked in particular by antibodies to 2 integrins, CD69, and apolipoprotein A-I; the last of these is produced by the liver and is an “inverse” or “negative” acute-phase protein whose level is decreased under the influence of IL-1, TNF , and IL-6 (3). The generation of the active form of IL-1 is controlled by caspase 1 (IL-1 –converting enzyme). Once produced, extracellular IL-1, membraneassociated IL-1 , or soluble IL-1 binds to the functional IL-1 receptor I (IL-1RI). IL-1RII is expressed at the surface of cells which also express IL-1RI. However, the binding of IL-1 to IL-1RII does not transduce any signal, since IL-1RII is a decoy receptor. Furthermore, the shed form of IL-1RII, soluble IL-1RII (sIL-1RII), also binds IL-1, thus diminishing the concentrations of active IL-1 and IL-1 that bind to IL-1RI (4). The first evidence and proof of the concept of true receptor antagonists to IL-1 (IL-1Ra) arose from studying the biology of IL-1, when studies of IL-1 binding to cells revealed a competitive mechanism at the receptor level after purifying the factor isolated from urine (5). In fact, biologic activity inhibitory to IL-1 and IL-1 was originally found in vivo in the urine of febrile patients with juvenile rheumatoid arthritis or monocytic leukemia and in vitro in culture supernatants from monocytes stimulated with immune complexes (6–8). Subsequently, IL-1Ra was sequenced and cloned (9,10). While expressed predominantly by monocytes, but by many other cells as well, IL-1Ra is unique in the cytokine network, in that it binds competitively to IL1RI but does not engage the formation of a high-affinity trimolecular complex with IL-1RI and IL-1R accessory protein. The latter mechanism hampers the transduction of IL-1 signaling. The complexity of the interaction among IL-1, IL-1R, and sIL-1R is highlighted by the fact that the inhibitory activity of IL-1Ra is enhanced by sIL-1RII, but hindered by sIL-1RI (11). Consequently, the use of sIL-1RII could also be an important therapeutic approach. IL-1Ra presents the advantage of inhibiting both IL-1 and IL-1 , which implies that it is potentially efficient at several levels (i.e., sIL-1 and cell-associated IL-1, the latter being predominantly IL-1 ). It should be remembered that 90% of the IL-1RI binding sites need to be occupied for blockade of the biologic activities of IL-1. In vitro, natural IL-1Ra as well as recombinant IL-1Ra block bone resorption and prostaglandin Jean-Michel Dayer, MD: University Hospital, Geneva, Switzerland; Barry Bresnihan, MD, FRCP: St. Vincent’s University Hospital, Dublin, Ireland. Address correspondence and reprint requests to Jean-Michel Dayer, MD, Immunology/Allergy Division, University Hospital, 1211 Geneva 14, Switzerland. E-mail: jean-michel.dayer@hcuge.ch. Submitted for publication October 4, 2001; accepted in revised form November 2, 2001.