Excessive interleukin-1 signaling determines the development of Th1 and Th17 responses in chronic inflammation.код для вставкиСкачать
ARTHRITIS & RHEUMATISM Vol. 62, No. 2, February 2010, pp 320–322 DOI 10.1002/art.27242 © 2010, American College of Rheumatology EDITORIAL Excessive Interleukin-1 Signaling Determines the Development of Th1 and Th17 Responses in Chronic Inflammation Leo A. B. Joosten 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: firstname.lastname@example.org. Submitted for publication September 30, 2009; accepted in revised form October 26, 2009. 320 EDITORIAL 321 Figure 1. Th1 and Th17 responses in human autoimmune diseases. After stimulation of macrophages or dendritic cells, proinflammatory cytokines, such as tumor necrosis factor ␣ (TNF␣), interleukin-1␤ (IL-1␤), IL-12, and IL-18 are produced. Thereafter, Th1 cells are generated from naive Th0 cells under the influence of interferon-␥ (IFN␥), IL-12, and IL-18. IFN␥ leads to further activation of macrophages/dendritic cells and fibroblasts by enhancing the levels of IL-1 receptor (IL-1R) expression. Apart from TNF␣ and IL-1␤, myeloid cells also produce IL-6 after IL-1 exposure, which in turn, regulates IL-1R expression on naive Th0 cells in a STAT-3–dependent manner. When both IL-1 and IL-23 are present, Th0 cells differentiate toward Th17 cells. Th17 cells produce both TNF␣ and IL-17 after exposure to IL-1. Th17 cells can switch to Th1 cells via an IL-12/STAT-4– dependent mechanism. IL-1 is needed for the phenotypical conversion of natural T regulatory cells, or Treg cells, to Th17, and it thereby contributes to elevated Th17 responses. Blockade of the IL-1R by IL-1 receptor antagonist (IL-1Ra) results in suppression of both the Th1 response and the Th17 response. TLR ⫽ Toll-like receptor; APC ⫽ antigen-presenting cell; Fibro ⫽ fibroblast. several autoimmune diseases is acknowledged, since the essential contribution of IL-1 to Th17 responses has been demonstrated. In this issue of Arthritis & Rheumatism, Lamacchia and colleagues demonstrate that excessive IL-1 signaling contributes to the development of enhanced Th1 and Th17 responses (19). Lamacchia and colleagues have elegantly shown that myeloid cell–specific IL-1Ra– deficient mice generate increased Th1 and Th17 responses to type II collagen, which results in the aggravation of arthritis and joint destruction. These results are consistent with those of previous studies showing that Th1 cells contribute to the severity of CIA. Both interferon-␥ (IFN␥) and IL-12 have been revealed to contribute to the development of CIA and, after the onset of disease, to control the severity of the arthritis (20,21). Excessive IL-1 signaling caused by a lack of IL-1Ra production by myeloid cells may result in enhanced Th1 responses. IL-1 itself stimulates the production of both IL-12 and IL-18 by macrophages and dendritic cells, while IL-12/IL-18 synergistically stimulates the induction of IFN␥ by Th1 cells (22). Lamacchia and colleagues showed that a shift from a Th1 response to a Th17 response occurred during the course of CIA in mice lacking IL-1Ra in myeloid cells. However, it has been reported that Th17 cells can shift to Th1 cells via an IL-12/STAT-4–dependent mechanism, and this conversion may explain the presence of both Th1 and Th17 cells in CIA (23). IL-1Ra deficiency in myeloid cells results in a higher Th17 response to type II collagen. These data are consistent with findings that IL-1 is a major cytokine for the generation of Th17 from naive T cells. It was also shown that IL-1 is critical for the phenotypical conversion of natural Treg cells to Th17 cells, which was independent of FoxP3 down-regulation (13). These data indicated that excessive IL-1 activity contributes to the generation of Th17 cells originating from both naive T cells and Treg cells (Figure 1). A deficiency in IL-1Ra leads to autoinflammatory diseases, both in mice and humans. As indicated previously, mice defective in the production of IL-1Ra spontaneously develop arthritis, vasculitis, and psoriasislike skin inflammation (5). Of great importance, it was demonstrated very recently that humans bearing a mutation in the IL1RN gene develop a severe autoinflammatory syndrome (24). These patients expressed reduced levels of IL-1Ra messenger RNA and absent production of IL-1Ra protein, and these features resulted in life-threatening systemic inflammation with bone and skin involvement. Peripheral blood mononuclear cells (PBMCs) from individuals bearing the IL1RN mutation produced significantly more IL-6, IL-8, and TNF␣ than did healthy control PBMCs after stimulation with IL-1␤. Consistent with preclinical reports, skin biopsy tissues from these patients revealed enhanced expression of Th17 and IL-17 as compared with control skin. Nearly all patients had bone abnormalities 322 JOOSTEN and enhanced numbers of osteoclasts, indicating a disproportionate activity of IL-17. As might be predicted, treatment of these patients with anakinra (recombinant human IL-1Ra) resulted in a remarkably rapid clinical response. Clinical studies examining the blockade of IL-1 receptor signaling in RA patients taking anakinra have been performed, and recently, a study evaluating the neutralization of IL-1␤ by anti–IL-1␤ antibodies in RA patients was reported (25). Neither strategy resulted in an impressive improvement in the disease, although this was predicted from the results of the preclinical reports. It remains a matter of debate whether complete inhibition of IL-1 activity was obtained in these clinical trials. Considering the critical role of IL-1 in the development of Th17 responses, as discussed above, it is still remarkable that IL-1 targeting has not been effective thus far in RA patients. These results may also suggest that RA is not a predominantly T cell (Th1 and/or Th17)–driven disease, but that other mechanisms are involved in the pathogenesis of RA. 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