Synergistic activity of interleukin-4 and interleukin-10 in suppression of inflammation and joint destruction in rheumatoid arthritis (2001)

Rheumatoid arthritis (RA) is a disease dominated by joint inflammation, accompanied by several peripheral inflammatory manifestations (1). Although the etiology of RA is still not fully understood, the pathogenesis is known to involve chronic synovitis leading to destruction of joint tissues (in particular, cartilage and bone) and consequently, serious impairment of joint function (2). Patients also exhibit features of systemic inflammation (such as marked acute-phase responses), and the disease is associated with autoimmune responses, the latter being most clearly displayed in the production of autoantibodies against the IgG Fc regions (rheumatoid factor) (3). The important role of T helper cells, macrophages, dendritic cells (DC), and B cells in local tissue destruction in RA has been described extensively (4–7) (summarized in Figure 1). Macrophages and DC in the RA joint contribute strongly to inflammation by the production of proinflammatory mediators, uptake of (auto-)antigen, and presentation of peptides of processed antigen to T helper cells by class II major histocompatibility complex (MHC) molecules (HLA– DR1 and HLA–DR4, which are linked to RA) together with costimulatory molecules. In addition to the cell–cell contact of T helper cells with macrophages and DC, there are a number of factors that cause costimulation of T helper cells (e.g., interleukin-7 [IL-7], IL-12, IL-15, and IL-18) in the joints of RA patients (8–11). A predominance of Th1 cell activity (defined by interferon-g [IFNg] production) and low Th2 cell activity (defined by IL-4 production) have been demonstrated in RA joints (12–14). This Th1/Th2 imbalance has been shown to strongly enhance activation of macrophages, DC, and B cells by cell–cell contact and secretion of cytokines (15–17). B cells are stimulated to differentiate and produce antigen-specific immunoglobulins, in particular, IgG (3,5). IgG interacts with antigen to form immune complexes, and its Fc constant region binds to Fcg receptors (FcgR), causing activation of macrophages and DC by receptor crosslinkage (18). Apart from activation, this leads to increased and very efficient uptake of antigen, presentation of arthritogenic epitopes, and an increase or persistence of activation of inflammatory cells, and consequently, maintenance or stimulation of the inflammatory cascade. In addition, several other cell types, such as synovial fibroblasts and neutrophils, have been shown to increase joint inflammation and joint destruction (19,20). As a consequence of the above inflammatory response, different cell types in the synovial tissue (ST), articular cartilage, and bone are transformed and destroyed by several mediators, such as cytokines (IL-1b, tumor necrosis factor a [TNFa], IL-15, IL-17), metalloproteinases (matrix metalloproteinase 1 [MMP-1] and MMP-3), and oxygen radicals (10,21–25). This ultimately results in serious impairment of joint function. Several antiinflammatory mechanisms in response to the proinflammatory activity are activated in the RA joint in an attempt to control the dysregulated (auto)immune reactivity. These include the production of cytokines with antiinflammatory properties, such as IL-10, IL-13, and transforming growth factor b, present Supported by the Nationaal Reumafonds (the Dutch League against Rheumatism). Joel A. G. van Roon, PhD, Floris P. J. G. Lafeber, PhD, J. W. J. Bijlsma, PhD, MD: University Medical Center Utrecht, Utrecht, The Netherlands. Address correspondence and reprint requests to Joel A. G. van Roon, PhD, Department of Rheumatology and Clinical Immunology (F01.127), University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands. Submitted for publication May 11, 2000; accepted in revised form August 26, 2000.