The process of identifying and understanding cytokines: from basic studies to treating rheumatic diseases

This is a historical overview seen from a personal angle. It covers the insights made during the past 20 years into the destructive processes of rheumatoid arthritis (RA) related to cytokines. The biochemical knowledge of the matrix components (i.e. collagen) and enzymology (i.e. collagenase) available in the 1950s led to the identification of cells from synovial tissue producing collagenase (fibroblast-like cells) and their interaction with other immune cells, i.e. monocyte-macrophages (Mφ) and lymphocytes (1976–1979). This insight led to the isolation of soluble factors produced by Mφ, such as interleukin-1 (IL-1) and TNF, the principal cytokines inducing collagenase and PGE2 in many target cells (i.e. synovial fibroblasts, chondrocytes, bone-derived cells) (1981–1985). Further advances resulted from observations that, in clinical conditions (i.e. leukaemia, juvenile RA), a remission of fever and inflammation may occur spontaneously and that tissue catabolism may persist despite the absence of systemic inflammation; this gave rise to the concept and identification of endogenous cytokine inhibitors (i.e. IL-1 receptor antagonist and TNF soluble receptor) (1984–1989). The fourth milestone was the observation that the production of IL-1 and TNF by Mφ was induced mainly by direct contact with lymphocytes, prompting studies of the ligands and counter-ligands on Mφ and lymphocytes as well as inhibitors involved in this cell–cell contact, some of these inhibitors being involved in lipid metabolism and acute-phase proteins (HDL-apo A-1).