ABSTRACT
Inflammation is a normal response of living tissues to mechanical injury, invasion by microorganisms, and chemical toxins. The main goal of the inflammatory response is to protect the organism by getting rid of the initial cause of cell injury (e.g. microorganisms or toxins) and the consequences of such injury (e.g. necrotic cells and tissues), and in turn to initiate mechanisms aimed at repairing surrounding tissues that were damaged by injury. Inflammation has to be tightly controlled in time and space to avoid detrimental developments such as those seen in sepsis and chronic inflammatory diseases including rheumatoid arthritis (RA). Indeed, in chronic inflammation, which is an inflammation of prolonged duration, tissue destruction and attempts at repair occur simultaneously. In RA, the outcome is joint cartilage and bone destruction together with accumulation of fibrotic tissue due to synovial cell proliferation and infiltration, angiogenesis, and fibrosis. It has been assumed for a long time that the proinflammatory cytokines tumor necrosis factor (TNF) and interleukin-1b (IL-1b) play an important part in
RA progression. This was confirmed since inhibitors of these cytokines are now successfully used for clinical treatment. Indeed, to restrain inflammation, proinflammatory reactions are closely interconnected with counterregulatory anti-inflammatory pathways. In the extracellular space this function is fulfilled by specific inhibitors generated by the shedding of cell surface receptors, e.g. soluble TNF receptors, soluble IL-1 receptor II and IL-1 receptor accessory protein, and the release of secreted IL-1 receptor antagonist (sIL-1Ra). All these effectors are mainly produced by monocytes/macrophages, which together with T lymphocytes, are an important part of cellular infiltrate of joints in RA. This chapter reviews the state of the art of the mechanisms underlying the production of proinflammatory cytokines and cytokine inhibitors in chronic inflammation.
