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

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Vol. 62, No. 2, February 2010, pp 320–322
DOI 10.1002/art.27242
© 2010, American College of Rheumatology
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:
Submitted for publication September 30, 2009; accepted in
revised form October 26, 2009.
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
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
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
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.
Dr. Joosten drafted the article, revised it critically for important intellectual content, and approved the final version to be published. He had full access to all of the data in the study and takes
responsibility for the integrity of the data and the accuracy of the data
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