?The?Journal?of?Clinical?Investigation http://www.jci.org Volume 118 Number 11 November 2008
Evidence that cytokines play
a role in rheumatoid arthritis
Fionula M. Brennan1 and Iain B. McInnes2
1Kennedy Institute of Rheumatology, Imperial College London, London, United Kingdom. 2Centre for Rheumatic Diseases,
Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow, United Kingdom.
RA is a chronic autoimmune disease with 1% prevalence in the
industrialized world. It comprises a syndrome of pain, stiffness,
and symmetrical synovitis (inflammation of the synovial mem-
brane) of diarthrodial joints (freely moveable joints such as the
knee) that leads to articular destruction, functional decline, and
substantial comorbidity in the cardiovascular, neurologic, and
metabolic systems. Therapeutic approaches used previously relied
on disease-modifying antirheumatic drugs (DMARDs) such as
methotrexate and sulfasalazine that had only partial clinical ben-
efit and were associated with significant toxicity. More recently,
biologic therapeutics have revolutionized treatment and have aris-
en as a consequence of studies aimed at understanding the critical
effector pathways operating in the disease. Extensive genetic and
pathogenetic studies indicate dysregulation in both innate and
adaptive immune compartments. These lead to an elaboration of
autoantibody responses and dyslipidemia, which might predate
clinical disease onset by up to a decade. Transition occurs thereaf-
ter to articular localization via mechanisms as yet unknown, and
this leads to chronic synovitis.
RA synovial membrane contains activated B and T cells, some-
times organized into germinal center–like structures, plasma cells,
mast cells, and particularly activated macrophages, all recruited via
an intense neovascularization process with associated lymphan-
giogenesis. It is also recognized that host tissue cells (activated
synovial fibroblasts, chondrocytes, and osteoclasts) are involved,
mediating cartilage and bone destruction as well as feeding back to
promote perpetuation of inflammation. The recruitment, activa-
tion, and effector function of each of these contributor lineages is
directed principally by a network of cytokines (Figure 1).
The role of cytokines in RA
The appreciation of the role played by cytokines in RA patho-
genesis reflects (arguably) the most comprehensive analysis of
pathologic cytokine function in a chronic inflammatory disease
in recent years (reviewed in refs. 1–3). The availability of diseased
tissue from the pathogenic site (synovial joint) has both facili-
tated the investigation and enabled identification of the role of
key molecules involved in the pathogenesis of this disease. In this
Review, we provide a historical perspective outlining those stud-
ies that identified the pivotal role of TNF-α in the pathogenesis
of RA, leading to the first clinical trials of a biological therapeu-
tic in this disease. Thereafter, looking forward, we address other
cytokines that might play a role in the disease, including those
contained in the IL-1, IL-6, and IL-23 superfamilies (as members
of these cytokine superfamilies are the ones with most informa-
tion available), together with selected cytokines that bind a recep-
tor containing the common γ-chain (γc). Importantly, the nature
of rheumatoid disease has changed since both authors started
their studies more than 20 years ago. This resulted in part from
more aggressive intervention initiated earlier and is reflected in
improved functional outcomes and reduced erosive progression
manifest in fewer arthroplasties (joint replacements). Important-
ly, RA synovial tissue that is now obtained for ex vivo analysis is
generally less cellular and inflammatory than previously analyzed
tissue (authors’ unpublished observations). Furthermore, because
it is obtained from joint replacement surgery from “end-stage”
disease, it might not be useful for identifying factors important
in the early phases of disease. These facts have implications for
identifying novel targets in this disease and might also contrib-
ute to the differences recently observed between results of studies
in vitro and in mouse models and those on human diseased tis-
sue. Nevertheless, we propose that novel therapeutic targets and
further improvement in outcomes might be offered by continued
elucidation of the effector biology of cytokines.
TNF-α and structurally related cytokines
TNF-α was identified in 1975 as the factor in serum isolated from
endotoxin-treated mice that induced necrosis of a methylcho-
lanthrene-induced murine sarcoma (4). It soon became appar-
ent that TNF-α had other effects, including the ability to induce
signs and symptoms of shock and multiorgan damage (5) via
proinflammatory effects on vascular endothelium (reviewed in
ref. 6). The demonstration that TNF-α played a key role in RA fol-
lowed from the demonstration of its potential to degrade cartilage
(7) and bone (8) in vitro. Moreover, it was shown using dissociated
RA synovial mononuclear cell cultures that TNF-α and several
Nonstandard?abbreviations?used: APRIL, a proliferation-inducing ligand; BLyS,
B lymphocyte stimulator; γc, common γ-chain; CIA, collagen-induced arthritis;
DMARD, disease-modifying antirheumatic drug; FLS, fibroblast-like synoviocyte;
IL-1Ra, IL-1 receptor antagonist; LT-β, lymphotoxin-β.
Conflict?of?interest: The authors have declared that no conflict of interest exists.
Citation?for?this?article: J. Clin. Invest. 118:3537–3545 (2008). doi:10.1172/JCI36389.
3538?The?Journal?of?Clinical?Investigation http://www.jci.org Volume 118 Number 11 November 2008
other proinflammatory cytokines, including IL-1 (9), IL-6 (10),
GM-CSF (11), and IL-8 (12), were spontaneously and chronically
produced over a five-day culture period (13, 14). Importantly, if
TNF-α bioactivity was blocked in these cultures, the spontaneous
production of both IL-1 protein and IL1B mRNA was markedly
reduced and IL-1 bioactivity was neutralized (13). This suggested
that the presence of many of these cytokines was not random, but
that a network or hierarchy controlled their expression. Consis-
tent with this idea, it was subsequently shown that blockade of
TNF-α also inhibited the spontaneous production of GM-CSF
(11) (which is important for the induction and maintenance of
MHC class II expression on APCs in the synovial fluid and tissue)
and the expression of the proinflammatory cytokine IL-6 and the
chemokine IL-8 (15). The pathogenic effects of TNF-α relevant to
RA disease are illustrated in Figure 2.
It was soon shown, using immunohistochemistry, that TNF-α
and receptors for TNF-α (TNFRs) (16, 17) were expressed in human
rheumatoid joint tissue and, using the collagen-induced arthritis
(CIA) model of RA, that administration of an mAb specific for
mouse TNF-α after disease onset ameliorated both inflammation
and joint damage (18). Separately, Kollias and colleagues found
that transgenic mice expressing the modified human TNFA gene
(with replacement of the 5′-UTR regulatory sequences) spontane-
ously developed peripheral arthritis. This arthritis was character-
ized by increased human TNF-α protein, joint inflammation, bone
erosion, and cartilage destruction (all hallmarks of RA), and dis-
ease could be ameliorated with antibodies specific for human, but
not mouse, TNF-α (19). Together these data provided the rationale
for developing therapeutics that block TNF-α.
In 1992, the first open-label trial of a TNF-α blocking agent was
initiated at the Kennedy Institute of Rheumatology Division, Unit-
ed Kingdom; 20 patients with active RA were treated with inflix-
imab (Remicade), a chimeric antibody specific for human TNF-α.
Treatment with infliximab substantially reduced the signs and
symptoms of disease, levels of C-reactive protein (CRP) in the serum,
and the erythrocyte sedimentation rate (ESR) (20). This result was
confirmed in other multicenter placebo-controlled trials, together
with the observation that therapeutic efficacy was enhanced when
infliximab was coadministered with methotrexate. This led eventu-
ally to FDA approval of the drug for the treatment of RA (21, 22).
Importantly a subsequent two-year trial indicated that this therapy
led to retardation or arrest of both joint space narrowing and bone
erosion (23). In addition to infliximab, two other drugs that func-
tion as TNF-α blockers are licensed: etanercept (Enbrel), which is a
fusion protein comprising human soluble TNFR linked to the Fc
component of human IgG1, and adalimumab (Humira), which is a
fully human antibody specific for human TNF-α (Table 1).
TNF-α is now recognized as mediating a wide variety of effector
functions relevant to the pathogenesis of RA, including endothelial
cell activation and chemokine amplification, leading to leukocyte
Cytokine targets in RA. This figure summarizes the cellular interactions believed to be of importance in the pathogenesis of RA and describes the
interaction among macrophages, T cells, B cells, and nonhematopoietic cells (fibroblasts, connective tissue cells, and bone). These interactions
are facilitated by the actions of cytokines released from the activated cells that then, through both autocrine (feedback on same cell) and para-
crine (via other cell types) mechanisms, induce the production of other proinflammatory cytokines, which together contribute to the pathogenesis
of this disease. Based on ex vivo studies from diseased tissue and in vivo studies on animal models, those cytokines with pathogenic potential
have been identified and biological therapies developed to block their action. This figure identifies those therapeutic modalities and the stage in
clinical development that these interventions have reached. sIL-6R, soluble IL-6 receptor.
?The?Journal?of?Clinical?Investigation http://www.jci.org Volume 118 Number 11 November 2008
text of an inflammatory cytokine milieu supports
de novo differentiation of IL-17-producing T cells.
104. Bettelli, E., et al. 2006. Reciprocal developmental
pathways for the generation of pathogenic effector
TH17 and regulatory T cells. Nature. 441:235–238.
105. Mangan, P.R., et al. 2006. Transforming growth
factor-beta induces development of the T(H)17
lineage. Nature. 441:231–234.
106. McGeachy, M.J., and Cua, D.J. 2008. Th17 cell dif-
ferentiation: the long and winding road. Immunity.
107. Ouyang, W., Kolls, J.K., and Zheng, Y. 2008. The
biological functions of T helper 17 cell effector
cytokines in inflammation. Immunity. 28:454–467.
108. Yang, L., et al. 2008. IL-21 and TGF-beta are
required for differentiation of human T(H)17 cells.
109. Krueger, G.G., et al. 2007. A human interleukin-
12/23 monoclonal antibody for the treatment of
psoriasis. N. Engl. J. Med. 356:580–592.
110. McInnes, I.B., et al. 1996. The role of interleukin-15
in T-cell migration and activation in rheumatoid
arthritis. Nat. Med. 2:175–182.
111. McInnes, I.B., Leung, B.P., Sturrock, R.D., Field,
M., and Liew, F.Y. 1997. Interleukin-15 mediates
T cell-dependent regulation of tumor necrosis fac-
tor-alpha production in rheumatoid arthritis. Nat.
112. Ferrari-Lacraz, S., et al. 2004. Targeting IL-15
receptor-bearing cells with an antagonist mutant
IL-15/Fc protein prevents disease development and
progression in murine collagen-induced arthritis.
J. Immunol. 173:5818–5826.
113. Ruchatz, H., Leung, B.P., Wei, X.Q., McInnes, I.B.,
and Liew, F.Y. 1998. Soluble IL-15 receptor alpha-
chain administration prevents murine collagen-
induced arthritis: a role for IL-15 in development
of antigen-induced immunopathology. J. Immunol.
114. Baslund, B., et al. 2005. Targeting interleukin-15 in
patients with rheumatoid arthritis: a proof-of-con-
cept study. Arthritis Rheum. 52:2686–2692.
115. Ponchel, F., et al. 2005. Interleukin-7 deficiency in
rheumatoid arthritis: consequences for therapy-
induced lymphopenia. Arthritis Res. Ther. 7:R80–R92.
116. Harada, S., et al. 1999. Production of interleukin-7
and interleukin-15 by fibroblast-like synoviocytes
from patients with rheumatoid arthritis. Arthritis
117. van Roon, J.A., et al. 2005. Increased intraarticu-
lar interleukin-7 in rheumatoid arthritis patients
stimulates cell contact-dependent activation of
CD4(+) T cells and macrophages. Arthritis Rheum.
118. Long, D., Blake, S., Song, X.Y., Lark, M., and Loeser,
R.F. 2008. Human articular chondrocytes produce
IL-7 and respond to IL-7 with increased produc-
tion of matrix metalloproteinase-13. Arthritis Res.
119. Timmer, T.C., et al. 2007. Inflammation and ecto-
pic lymphoid structures in rheumatoid arthritis
synovial tissues dissected by genomics technology:
identification of the interleukin-7 signaling path-
way in tissues with lymphoid neogenesis. Arthritis
120. Weitzmann, M.N., Cenci, S., Rifas, L., Brown, C.,
and Pacifici, R. 2000. Interleukin-7 stimulates
osteoclast formation by up-regulating the T-cell
production of soluble osteoclastogenic cytokines.
121. van Roon, J.A., et al. 2007. Persistence of interleukin
7 activity and levels on tumour necrosis factor alpha
blockade in patients with rheumatoid arthritis.
Ann. Rheum. Dis. 66:664–669.
122. Jungel, A., et al. 2004. Expression of interleukin-21
receptor, but not interleukin-21, in synovial fibro-
blasts and synovial macrophages of patients with
rheumatoid arthritis. Arthritis Rheum. 50:1468–1476.
123. Li, J., Shen, W., Kong, K., and Liu, Z. 2006.
Interleukin-21 induces T-cell activation and
proinflammatory cytokine secretion in rheuma-
toid arthritis. Scand. J. Immunol. 64:515–522.
124. Andersson, A.K., Feldmann, M., and Brennan, F.M.
2008. Neutralizing IL-21 and IL-15 inhibits pro-
inflammatory cytokine production in rheumatoid
arthritis. Scand. J. Immunol. 68:103–111.
125. Young, D.A., et al. 2007. Blockade of the inter-
leukin-21/interleukin-21 receptor pathway ame-
liorates disease in animal models of rheumatoid
arthritis. Arthritis Rheum. 56:1152–1163.
126. Goekoop-Ruiterman, Y.P., et al. 2008. Clinical and
radiographic outcomes of four different treatment
strategies in patients with early rheumatoid arthri-
tis (the BeSt study): a randomized, controlled trial.
Arthritis Rheum. 58:S126–S135.