Tumor Necrosis Factor
F Atzeni, Queen Mary University of London, London, UK; Rheumatology Unit, L.Sacco University Hospital, Milan, Italy
P Sarzi-Puttini, Rheumatology Unit, L.Sacco University Hospital, Milan, Italy
© 2013 Elsevier Inc. All rights reserved.
This article is a revision of the previous edition article by TH Rabbitts, volume 4, p 2081, © 2001, Elsevier Inc.
Glossary
Atherosclerosis and heart failure Cardiovascular
involvement.
Bone damage Bone alterations and resorption.
Introduction
Tumor necrosis factor (TNF), a 17 kDa protein consisting of
157 amino acids, is a homotrimer in solution, and its bioactiv­
ity is mainly regulated by soluble TNFα-binding receptors. In
humans, the gene maps to chromosome 6.
TNF is mainly produced by activated macrophages, T lym­
phocytes, and natural killer (NK) cells, although it is also
expressed at lower levels by various other cells, including fibro­
blasts, smooth muscle cells, and tumor cells. Cellular TNF is
synthesized as pro-TNF (26 kDa), which is bound to the mem­
brane and released upon the cleavage of its pro-domain by the
TNF-converting enzyme (TACE). TNFα acts via two distinct
receptors (TNFR-1 and TNFR-2) but, although its affinity for
TNFR-2 is 5 times higher than that for TNFR-1, the latter
initiates most of its biological activities. TNFR-1 (p55) is
expressed on all cell types, whereas the expression of TNFR-2
(p75) is mainly confined to immune cells. The main difference
between the two receptors is that TNFR-2 does not have the
death domain (DD) possessed by TNFR-1. TNFR-1 plays a dual
role: it is not only involved in inducing apoptosis, but can also
transduce cell survival signals. The signaling pathways are well
defined, but the regulation of life/death signaling is still poorly
understood.
TNF is involved in a large number of pathological and
physiological pathways:
1. Low levels may help maintain homeostasis by regulating
the body’s circadian rhythm, and promote the remodeling
or replacement of injured and senescent tissue by stimu­
lating fibroblast growth.
2. It plays a pivotal role in the pathogenesis of rheumatic
diseases such as rheumatoid arthritis (RA), Crohn’s dis­
ease (CD), psoriatic arthritis (PsA), and ankylosing
spondylitis (AS).
3. It is involved in bone damage and resorption.
4. It is involved in host defense and tumor surveillance.
5. It plays a role in heart failure, and promotes the dyslipi­
demia and insulin resistance involved in initiating the
atherosclerosis that leads to plaque rupture and acute
myocardial infarction (AMI).
Brenner’s Encyclopedia of Genetics, 2nd edition, Volume 7 doi:10.1016/B978-0-12-374984-0.01594-1
Osteoclasts and osteoblasts Cells involved in bone
remodeling.
Rheumatoid arthritis Autoimmune rheumatic disease.
Tumor necrosis factor Proinflammatory cytokine.
The Role of TNF in the Pathogenesis of RA and Bone
Damage
Pathogenesis of RA
Proinflammatory cytokines such as TNF and interleukin (IL)-1β
play a key role in the pathogenesis of RA. The synovial mem­
brane of RA patients is hyperplastic, highly vascularized, and
infiltrated by inflammatory cells. CD4+ T lymphocytes play an
important role because, when activated by an antigen, they
stimulate monocytes, macrophages, and synovial fibroblasts
to produce IL-1, IL-6, and TNF; they also secrete matrix metal­
loproteinases (MMPs) as a result of cell-surface signaling by
means of CD69 and CD118, and by means of the release of
soluble mediators such as interferon (IFN)-γ, IL-1, IL-6, IL-17,
and TNF. Activated CD4+ T cells stimulate B cells by means of
cell–cell contacts, and bind α sub 1 and β sub 2 integrin, CD 40
ligand, and CD28 to produce immunoglobulins (Ig’s), includ­
ing rheumatoid factor (RF). They also express the receptor
activator of NF-κB (RANK), which stimulates osteoclastogen­
esis via the RANK ligand (RANKL). Activated macrophages,
lymphocytes, and fibroblasts can also stimulate angiogenesis,
which is responsible for the synovial hypervascularity of RA
patients. Synovial endothelial cells are activated and express
adhesion molecules that promote the recruitment of inflam­
matory cells. Finally, TNF induces the production of various
cytokines and stimulates fibroblasts to express adhesion mole­
cules that interact with the ligands on the surface of leukocytes
and increase the number of inflammatory cells. TNF has an
immunostimulatory role that can alter the balance of regula­
tory T cells. RA patients have high TNF levels in their synovial
fluid, which are localized to the junction between the inflam­
matory pannus and the healthy cartilage, and associated with
bone erosions.
Bone Damage
Animal studies have provided key evidence that antagonizing
TNF is a viable therapeutic strategy, and subsequent studies of
various anti-TNF blockers have shown that blocking TNF
improves the symptoms of RA patients and arrests bone
damage by affecting bone remodeling.
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230 Tumor Necrosis Factor
It regulates bone marrow levels of osteoclast precursors
directly by upregulating c-fms expression, and activates osteo­
clasts by enhancing RANK signaling mechanisms. The RANKL
pathway regulates osteoclast differentiation and function dur­
ing physiological bone remodeling, and RANKL promotes
osteoclastogenesis by binding to its cognate receptor on osteo­
clast precursor cells. Osteoprotegerin (OPG) is a soluble decoy
RANKL receptor that blocks RANKL’s pro-osteoclastogenic
activity. The RANK/RANKL pathway is also activated in patients
with inflammatory arthritis, thus leading to dysregulated bone
remodeling. The RANKL:OPG messenger RNA (mRNA) expres­
sion ratio is increased in RA synovial tissue, which indicates
that pro-osteoclastogenic conditions dominate within the joint
microenvironment.
TNF indirectly influences osteoclastogenesis by inducing
the expression of RANKL and macrophage colony-stimulating
factor (M-CSF) in bone marrow stromal cells of osteoblast
lineage.
TNF is considered an ‘upstream’ dominant proinflamma­
tory cytokine because anti-TNF antibodies significantly reduce
the IL-1 production of cultured synovial cells taken from
patients with RA. It also affects osteoblasts by inhibiting their
differentiation and maturation, thus leading to a decrease in
alkaline phosphatase and osteocalcin expression. Mice and
wild-type mice treated with exogenous TNF show increased
numbers of CD11b+ osteoclast precursor cells, an effect that
is independent of RANKL. In human disease, data from clinical
trials confirm that inhibiting TNF activity in RA patients effec­
tively protects against bone erosion. Although this is largely
due to the anti-inflammatory effects of TNF inhibition, other
possible mechanisms by which TNF inhibition decreases struc­
tural damage include a direct reduction of osteoclast-mediated
bone loss and an increase in osteoblast-mediated bone
formation.
The Role of TNF in Host Defense and Tumor Surveillance
Host Defense
TNF is released by activated macrophages, T lymphocytes, and
other immune cells in response to various infectious stimuli and,
among its other effects, it has antitumoral and antiviral activity,
mediates systemic inflammatory responses to infection and sep­
sis, and plays a crucial role in host responses to a number of
infections, especially those caused by Mycobacterium tuberculosis
and other intracellular pathogens.
TNF is essential for controlling intracellular pathogens as it
stimulates inflammatory cell recruitment to the infectious area,
and the formation and maintenance of the granulomas that
physically contain the infection. It acts as part of the immune
response to M. tuberculosis infection (TB) in conjunction with
IFN-γ by inducing macrophage activation, enhancing immune
cell recruitment, and increasing the chemokine expression of
macrophages by activating the NF-κB signaling pathway. TNF
also mediates cell death by inducing the caspase-mediated
apoptotic pathway.
These roles have been elucidated by murine models. In
TNF-deficient mice, inflammatory cell recruitment is delayed
and, even after their recruitment, the leukocytes fail to form
the organized granulomas necessary to contain infection.
Furthermore, once the granulomas have formed, the
administration of anti-TNF agents can lead to their regression
and enable the reactivation of latent TB. However, such treat­
ment is only one of many risk factors that predispose to the
development of TB.
Finally, TNF is involved in leukocyte trafficking and the
clearance of immune complex (IC). Bacterial infections have
always been the most common infections in our immunocom­
promised patients receiving anti-TNF therapy.
Tumor Surveillance
The exact relationship between TNF and cancer is unclear:
high-dose TNF has been used to treat some malignancies,
including melanoma and sarcoma, but it has also been sug­
gested that cancer-related cachexia could be treated using
anti-TNF agents, which indicates that TNF may play different
roles at different concentrations in the different stages of carci­
nogenesis. Similarly, anti-TNF therapy may have a spectrum of
effects on de novo malignancies, in situ carcinomas (CIS), and
pre-existing tumors, and so, given hypothetically increased risk
of new or recurrent malignancies in already affected patients,
researchers initially excluded them from randomized clinical
trials of anti-TNF therapy for RA. However, since then, a num­
ber of studies have shown that anti-TNF therapy does not
increase the risk of incident malignancy in RA patients,
although further investigations are still necessary to confirm
these findings.
The Role of TNF in Heart Failure and Atherosclerosis
Heart Failure
The expression of TNF is highly tissue-specific. Under normal
conditions, it is expressed in the spleen, liver, thymus, and
kidney but, following various types of stimulation (e.g., bacter­
ial sepsis), it can be expressed at extremely high levels. It has
also been shown that myocardial stress, and pressure and
volume overload, leads to large quantities of TNF in the
heart. The mechanisms by which TNF mediates cardiac injury
are not entirely clear, but it has been demonstrated that circu­
lating TNF levels inversely correlate with peak blood flow in
patients with heart failure, regardless of their age, ejection frac­
tion, or peak oxygen consumption. This suggests that TNF may
contribute to peripheral skeletal muscle weakness/fatigue in
such patients. With these theories in mind, a number of clinical
trials have studied the effects of TNFα inhibition in patients
with heart failure. However, the published data showed that
anti-TNF agents offer no benefit for various reasons, including
the fact that they have untoward effects in the setting of heart
failure and the possibility that the biological agents used in the
trials were intrinsically toxic.
Atherosclerosis
TNF promotes dyslipidemia and insulin resistance (both of
which are traditional risk factors for atherosclerosis), upregu­
lates adhesion molecules, which leads to the formation of fatty
streaks and the beginning of atherosclerosis, and is involved in
the inflammation that leads to plaque rupture, which is the
most frequent cause of acute myocardial infarct (AMI).

Inhibiting TNF in patients with RA may therefore reduce MI
rates by inhibiting one or more of these mechanisms, particu­
larly in those with a good clinical response.
TNF may also promote thrombophilia by encouraging
thrombotic events.
Conclusions
TNF is involved in various pathological and physiological path­
ways. The use of anti-TNF drugs to treat rheumatic diseases has
confirmed the relevance of this cytokine to their pathogenesis,
as well as to host defenses and cancer control. However, further
studies are required to improve our understanding of its role
and to answer some still open questions.
See also: Autoimmune Diseases; Cytokinesis; Immunological
Tolerance; Psoriasis.
Further Reading
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rheumatoid arthritis. The New England Journal of Medicine 344: 907–916.
Crum NF, Lederman ER, and Wallace MR (2005) Infections associated with tumor
necrosis factor-α antagonists. Medicine (Baltimore) 84: 291–302.
Tumor Necrosis Factor 231
Desai SB and Furst DE (2006) Problems encountered during anti-tumor necrosis factor
therapy. Best Practice & Research: Clinical Rheumatology 20: 759–760.
Dixon WG, Hyrich KL, Watson KD, et al. BSRBR Control Centre Consortium, Symmons
DP, BSR Biologics Register (2010) Drug-specific risk of tuberculosis in patients with
rheumatoid arthritis treated with anti-TNF therapy: Results from the British Society
for Rheumatology Biologics Register (BSRBR). Annals of the Rheumatic Diseases
69: 522–528.
Dixon WG, Watson K, Lunt K, et al. British Society for Rheumatology Biologics Register
Control Centre Consortium, Silman AJ, Symmons DPM (2006) Rates of serious
infection, including site-specific and bacterial intracellular infection, in rheumatoid
arthritis patients receiving anti-tumor necrosis factor therapy. Arthritis &
Rheumatism 54: 2368–2376.
Ferraccioli G and Gremese E (2004) Autoantibodies and thrombophilia in RA: TNF and
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Gremese E and Ferraccioli G (2011) The metabolic syndrome: The crossroads between
rheumatoid arthritis and cardiovascular risk. Autoimmunity Reviews 10: 582–589.
Grivennikov SI and Karin M (2011) Inflammatory cytokines in cancer: Tumour necrosis
factor and interleukin 6 take the stage. Annals of the Rheumatic Diseases 70
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diabetes: How does it compare and when does it start? Annals of the Rheumatic
Diseases 70: 881–883.
Sarzi-Puttini P, Atzeni F, Gerli R, et al. (2010) Cardiac involvement in systemic rheumatic
diseases: An update. Autoimmunity Reviews 9: 849–852.
Sarzi-Puttini P, Atzeni F, Shoenfeld Y, and Ferraccioli G (2005) TNF-alpha, rheumatoid
arthritis, and heart failure: A rheumatological dilemma. Autoimmunity Reviews 4(3):
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Scott DL and Kingsley GH (2006) Tumor necrosis factor inhibitors for rheumatoid
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