Targeting TNF and Its Family Members in Autoimmune/Inflammatory Disease

Tumor necrosis factor (TNF), a pleiotropic cytokine mainly produced by activated macrophages, modulates a wide range of biological functions in multiple tissues and organs. Besides its effects on tumor cell death, TNF is a key mediator of both acute and chronic inflammation. Since the description of TNF in the 1970s and through consideration of structural homologies, a total of 19 TNF-related cytokines have now been regrouped into a large family called the TNF ligand superfamily (TNFSF), whose members interact with TNF receptor superfamily (TNFRSF) members. More than 150,000 scientific publications (!) concerning TNF and its family members are available, demonstrating the strong interest of the scientific community in this molecule. Numerous studies implicating TNF family members in the pathophysiology of human autoimmune/inflammatory diseases have supported the emergence of TNF blocking agents developed for treatment of human disease, particularly over the last decade. These biotherapies, in the form of (I) chimeric, humanized, or human anti-TNF monoclonal antibodies or (II) fusion proteins involving a soluble TNF receptor, have been very successful in ameliorating disease signs and symptoms, especially in patients suffering from rheumatoid arthritis (RA) and Crohn's disease. Nonetheless, several aspects of these beneficial effects remain enigmatic. Moreover, the modulatory factors influencing TNF production by macrophages are not all known. Nevertheless, it is expected that over the next few years we will witness an increasing number of diseases for which TNF-blockade therapy is indicated. In this special issue, eleven papers including research articles, review articles, and clinical studies provide new information and interesting discussion regarding current questions related to this hot topic. In the first group of articles, interesting data is presented about TNF-blocking therapies and modulation of TNF generation by macrophages. Y. Lv et al. studied the nonneuronal cholinergic system existing in macrophages and show in a murine monocyte/macrophage cell line that bacterial lipopolysaccharide (LPS) exposure enhances autocrine acetylcholine production associated with an attenuation of TNF release. In this same cell line, K. Borzęcka et al. determined that, during high dose LPS stimulation, CD14 together with scavenger receptors is required for the binding of LPS but has a limited and dispensable contribution to TNF production. R. Cascão et al. recently identified gambogic acid as a simultaneous blocker of IL-1í µí»½ and TNF secretion and described here a beneficial anti-inflammatory effect of gambogic acid in rat antigen-induced arthritis. Interestingly, F. R. Spinelli et al. show that blocking TNF biological effects during RA …