Excessive interleukin‐1 signaling determines the development of Th1 and Th17 responses in chronic inflammation

Abstract

The proinflammatory cytokines tumor necrosis factor (TNF ) and interleukin-1 (IL-1) are considered to be key mediators in chronic autoimmune diseases such as rheumatoid arthritis (RA), Crohn’s disease, and multiple sclerosis (1). IL-1 and TNF have been linked to joint inflammation and cartilage and bone destruction in patients with RA (2,3). This is underscored in animal models in which human TNF has been overexpressed or the IL-1 receptor antagonist (IL-1Ra), the natural inhibitor of IL-1, has been deleted (4,5). Intriguingly, the latter model is strongly T cell–dependent. It has been shown that T cells are important in the IL-1Ra mouse model of spontaneous arthritis, since arthritis did not develop when mice had no functional T cells. Moreover, arthritis could be transferred to naive nude mice by injection of T cells isolated from arthritic IL-1Ra mice (6). Interestingly, IL-1Ra mice displayed increased levels of IL-17 after T cell stimulation, and the role of IL-17 in this arthritis model was further explored by crossing IL-1Ra mice with IL-17 mice (7,8). The lack of IL-17 completely abrogated the onset of disease, indicating a crucial role of IL-17 in the development of arthritis in IL-1Ra mice. Since the discovery of IL-17 in 1995, the role of this cytokine has been examined in several models of inflammation. IL-17 was originally believed to belong to the IL-1 family of proteins because of an overlap, although less potent, of biologic activities with IL-1 (9). Several studies have shown that IL-17 plays a role in the development of collagen-induced arthritis (CIA). Studies exploring the neutralization of IL-17 by antibodies or by the use of IL-17–deficient mice showed that IL-17 is involved in this model of autoimmune arthritis (10). Local overexpression of IL-17 during the onset of CIA demonstrated that IL-17 could aggravate cartilage and bone destruction (11). As indicated above, there are several current reports indicating that IL-17 contributes to autoimmune inflammation, but less potently as compared with IL-1. The dominant role of IL-1 in T cell processes was rediscovered by the demonstration of its role in the generation of Th17 cells. It should be remembered that IL-1 was initially named lymphocyte proliferation factor (1). Studies of autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE) demonstrated that IL-1 is crucial in the induction of Th17-producing cells (12). One study elegantly showed that IL-1 drives the development of pathogenic Th17 cells during the onset of arthritis in IL-1Ra mice (7). Of high interest was the finding that IL-1 signaling is crucial for the development and production of IL-17 and TNF by these Th17 cells (13). Very recently, it was demonstrated that predominantly Th17 cells express both of the IL-1 receptor components IL-1 receptor type I (IL-1RI) and IL-1 receptor accessory protein (IL-1RAcP) as compared with Th1 or Th2 cells (14). It is now commonly accepted that Th17 cells play a pathogenic role in several autoimmune diseases, including RA and multiple sclerosis (9). IL-1 has been demonstrated to be critical for the development of autoimmune arthritis. Blockade of endogenous IL-1, in particular IL-1 , was shown to prevent the onset of type II collagen–induced arthritis (CIA) in mice. Even full-blown CIA was impressively reduced after treatment with neutralizing anti–IL-1 antibodies (15,16). The strong IL-1 dependency of murine CIA was further demonstrated by elegant studies using either IL-1–knockout mice, caspase 1 (also known as IL-1 –converting enzyme) inhibitors, and caspase 1 gene–deficient mice (17,18). In models of EAE, it was also demonstrated that IL-1 signaling was decisive for the induction of chronic inflammation. IL-1RI gene– deficient mice were shown to be completely protected against EAE. Nowadays, the important role of IL-1 in Leo A. B. Joosten, PhD: Nijmegen Institute for Infection, Inflammation and Immunity, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. Address correspondence and reprint requests to Leo A. B. Joosten, PhD, Department of Medicine (463), Radboud University Nijmegen Medical Centre, Geert Grooteplein Zuid 8, 6525 GA, Nijmegen, The Netherlands. E-mail: l.joosten@aig.umcn.nl. Submitted for publication September 30, 2009; accepted in revised form October 26, 2009.