Báo cáo khoa học: Tumor necrosis factor receptor cross-talk docx

MINIREVIEW
Tumor necrosis factor receptor cross-talk
Petrus J. W. Naude
´
, Johan A. den Boer, Paul G. M. Luiten and Ulrich L. M. Eisel
Departments of Molecular Neurobiology and Biological Psychiatry, University of Groningen, The Netherlands
Introduction
Tumor necrosis factor-alpha (TNF-a) was discovered
 30 years ago as a product of immune activation. In the
last three decades, an impressive amount of knowledge
has been obtained regarding the biological functions of
TNF, as well as the signaling mechanisms engaged by its
receptors. TNF primarily occurs as a type II transmem-
brane protein of 26 kDa, which can be cleaved by the
metalloprotease TNF-a-converting enzyme to a 17 kDa
TNF protein that is biologically active in a soluble
homo-trimeric molecule of 51 kDa [1,2].
TNF exerts a broad range of biological effects via
two known transmembrane receptors that were discov-
ered  30 years ago [3]: the 55 kDa TNF receptor 1
(TNFR1), which is expressed ubiquitously on almost
all cell types; and the larger 75 kDa TNF receptor 2
(TNFR2), which under normal physiological conditions
is expressed typically at low levels in cells of the
immune system [4–8]. TNFR1 serves as the major
mediator of TNF-induced signaling pathways. TNFR1
signaling has pleiotropic functions such as activation
of nuclear factor kappaB (NF-jB) and induction of
apoptosis, both of which depend on the cellular envi-
ronment. The expression of TNFR2, however, is much
more limited to specific cell types compared with

Keywords
apoptosis; cross-talk; NF-kappa B; TNFR1;
TNFR2; TNF receptor associated factor
(TRAF); inhibitor of apoptosis (IAP); protein
kinase B/Akt; PI3K; RIP
Correspondence
U. L. M. Eisel, Department of Molecular
Neurobiology, University of Groningen,
P.O. Box 11103, NL-9700 CC Groningen,
The Netherlands
Fax: +31 50 363 2331
Tel: +31 50 363 2366
E-mail:
(Received 12 October 2010, revised 22
December 2010, accepted 7 January 2011)
doi:10.1111/j.1742-4658.2011.08017.x
Extensive research has been performed to unravel the mechanistic signaling
pathways mediated by tumor necrosis factor receptor 1 (TNFR1), by con-
trast there is limited knowledge on cellular signaling upon activation of
TNFR2. Recently published data have revealed that these two receptors
not only function independently, but also can influence each other via
cross-talk between the different signaling pathways initiated by TNFR1
and TNFR2 stimulation. Furthermore, the complexity of this cross-talk is
also dependent on the different signaling kinetics between TNFR1 and
TNFR2, by which a delicate balance between cell survival and apoptosis
can be maintained. Some known signaling factors and the kinetics that are
involved in the receptor cross-talk between TNFR1 and TNFR2 are the
topic of this review.
Abbreviations
ASK1, apoptosis signal-regulating kinase-1; c-IAP1 ⁄ 2, cellular inhibitor of apoptosis-1 ⁄ 2; IKK, IjB kinase; IjBa, inhibitor of kappa B-alpha;

JNK, c-Jun N-terminal kinase; NF-jB, nuclear factor kappa B; NIK, NF-jB-inducing kinase; RIP, receptor interacting protein; TNF, tumor
necrosis factor; TNFR1 ⁄ 2, tumor necrosis factor receptor 1 ⁄ 2; TRADD, TNF receptor-associated death domain; TRAF1 ⁄ 2 ⁄ 3,
TNF receptor-associated factor-1 ⁄ 2 ⁄ 3.
888 FEBS Journal 278 (2011) 888–898 ª 2011 The Authors Journal compilation ª 2011 FEBS
TNFR1. TNFR2 expression is restricted to specific
neuronal subtypes, and to oligodendrocytes, microglia
and astrocytes in the brain, to endothelial cells, and
certain T-cell subpopulations, including lymphocytes
(CD4
+
and CD8
+
T cells), cardiac myocytes, thymo-
cytes and human mesenchymal stem cells [9,10].
A large body of research has shown that TNF pos-
sesses the capacity for a great number of highly differ-
ent biological functions via its two receptors. Some
aspects regarding cross-talk between TNF receptors
and signaling cascades have been discussed in previous
review articles [11–13].
TNF signaling in immunity
The significant role of TNFR1 in immunity has been
shown in several studies in vivo. Flynn, et al. [14]
showed that TNFR1 is essential to protect mice against
tuberculosis infection, reactive nitrogen production by
macrophages and also proper granuloma functioning.
TNFR1- and TNF-deficient mice die from a fulminant
necrotizing encephalitis when orally infected with a
low-virulent strain of Toxoplasma gondii, whereas
TNFR2-deficient mice were unaffected [15]. Further-

more, it has been shown that TNFR1 is the TNF recep-
tor primarily responsible for initiating inflammatory
responses [16,17]. Kim et al. [18] published evidence
that CD4
+
and CD8
+
T cells depend on TNFR2 for
survival during clonal expansion in response to intracel-
lular bacterial pathogens, thus allowing larger accumu-
lation of effector cells and thereby optimizing
protection from apoptosis by inducing a substantial
generation of the antigen-specific memory T-cell popu-
lation pool. In an another study, it was found that
TNFR2- and TNF-knockout mice have delayed clear-
ance of hepatic replication-deficient adenovirus and
also decreased adenovirus-specific cytotoxic T-lympho-
cyte activity of intrahepatic lymphocytes. TNFR1
knockout mice did not display such effects, allowing
the conclusion that TNFR2 facilitates the generation of
antigen-specific cytotoxic T lymphocytes for antiviral
immune responses [19]. Also, TNFR2 knockout mice
had no CD8
+
T-cell-mediated lung injury associated
with clearance of experimental influenza virus, indicat-
ing that TNFR2 is important for the occurrence of
immunopathology in alveolar tissue [20]. However, in
another study, it was shown that TNFR2 activation by
insulin selectively killed autoreactive T cells derived

from the blood of type 1 diabetes patients, which did
not have an effect on other activated and memory
T-cell populations [21]. In summary, TNFR2 can play
a vital role in the maintenance of the delicate and com-
plex processes involved in immune system functioning.
TNF signaling in cellular survival
TNF in the nervous system exerts opposing effects via
TNFR1 and TNFR2 with respect to cell survival in
neuronal tissue exposed to traumatic insults (for fur-
ther details see Van Herreweghe et al. regarding
TNFR1-mediated cell death and survival signaling
mechanisms [22]). In a retinal ischemia mouse model,
both TNFR1 and TNFR2 were upregulated in neuro-
nal retinal cell layers a few hours after ischemia–reper-
fusion-induced retinal damage. Interestingly, TNFR1
aggravated neuronal death, whereas TNFR2 protected
against ischemic tissue destruction [23]. TNFR2 is also
necessary for TNF-a-induced regeneration of myelin-
forming oligodendrocyte precursor cells [24]. Specific
stimulation of TNFR1 in baboons caused local skin
necrosis, whereas TNFR2-specific stimulation had no
effect on skin necrosis [25]. Furthermore, in a large
human clinical trial it became clear that a TNF-neu-
tralizing antibody exacerbated symptoms when admin-
istered to patients with multiple sclerosis [26,27]. It has
also been shown in an in vivo heart failure model in
mice that TNFR1 has damaging effects on chamber
remodeling, systolic dysfunction and hypertrophy,
whereas TNFR2 proved to be cardioprotective in this
regard [28]. Although most of our knowledge with

respect to TNF signaling has been obtained in models
using TNFR1- and TNFR2 knockout mouse models,
as well as agonistic antibodies specifically stimulating
either one of the receptors, the coexistence and costi-
mulation of both receptors in an unaltered biological
system should be taken into consideration. It is possi-
ble that genetic modification to the animals might have
an influence on many different aspects of TNF signal-
ing. Deletion of the TNF might lead to alterations in
the balance of intricate signaling cascades, epigenetic
modifications and decreased soluble TNF receptors,
which also function as TNF inhibitors. Recently,
research has shown that cross-talk between TNFR1
and TNFR2 may take place which is controlled or
influenced by many factors, including cell type, intra-
cellular or extracellular environment, age, response to
injury, inflammation and the occurrence of NF-jB
activation [10].
TNFR1 signaling pathway
TNFR1 is activated via both membrane-bound and
soluble TNF [29]. The extracellular domain of TNFR1
contains three well-ordered cysteine-rich domains
(CRD1, -2 and -3) that characterize the TNF receptor
superfamily and a fourth membrane-proximal cysteine-
rich division [30]. The N-terminal cysteine-rich domain,
P. J. W. Naude
´
et al. TNF receptor cross-talk
FEBS Journal 278 (2011) 888–898 ª 2011 The Authors Journal compilation ª 2011 FEBS 889
known as the preligand binding assembly domain,

favors preassembly of TNFR1 into trimeric complexes.
The preligand binding assembly domain functions to
prevent spontaneous receptor autoactivation and is
also a prerequisite for ligand binding [31]. The intracel-
lular part of TNFR1 contains a protein–protein inter-
action region called the death domain [32]. After
ligand binding to the TNFR1, silencer of death
domain dissociates from the intracellular death domain
of TNFR1 and upon which the adapter protein TNF
receptor-associated death domain (TRADD) is
recruited that binds to the exposed death domain [33]
(Fig. 1). TRADD subsequently recruits other proteins
that are involved in downstream signaling, for exam-
ple, TNF receptor associate factor-2 (TRAF2). It was
believed that the death domain kinase, receptor-inter-
acting protein (RIP) can also interact with the death
domain of TNFR1 [34–36], however, recent research
has shown that RIP can be recruited to TNFR1 inde-
pendent of TRADD [37]. This membrane-bound
TNFR1 signaling complex (complex 1) rapidly initiates
signaling cascades leading to NF-jB and c-Jun N-ter-
minal kinase (JNK) ⁄ SAPK activation [35,38].
Upon NF-jB activation via TNFR1, TRAF2 or
TRAF5 and cellular inhibitor of apoptosis-1 ⁄ 2
(c-IAP1 ⁄ 2), together with E2, ubiquitin-conjugated
protein Ubc13 is associated with TRADD and RIP1
(Fig. 1). c-IAPs and both TRAF2 and TRAF5 con-
tribute to the ubiquitination of RIP1 upon TNFR1
stimulation via ubiquitin chains linked through
lysine 63 (K63) [39–41] (for more details see Wajant

and Scheurich [42]). Polyubiquitinated RIP1 can act
through signaling of MEKK3 and the TAK1 ⁄ TAB 2
complex to activate the catalytic IjB kinase (IKK)
complex, which is composed of three proteins, IKKa
(IKK1), IKKb (IKK2) and IKKc (NF-jB essential
modulator), leading to phosphorylation of inhibitor of
kappaB-alpha (IjBa), the NF-jB inhibitory protein.
Phospho-IjBa is then degraded via the ubiquitin–
proteasome pathway, allowing NF-jB to translocate
cIAP
RIP
TRAF2/5
TRADD
FADD
UBC13
NF-κ
κ
B transcripon
cIAP-1, cIAP-2,cFLIP,
TRAF1, and TRAF2
Ub
Ub
Ub
Caspase 8
Apoptosis
Nucleus
DD
TNFR1
TNF-α
Ub

Ub
Ub
RIP
TRAF2
P
NEMO
IKK
IKK
P50 P65
I
κ
B
α
P
P50 P65
Ub
Ub
Ub
DD
DD
Fig. 1. TNF-induced signaling via TNFR1.
DD, death domain; cIAP cellular inhibitor of
apoptosis; FADD, Fas-associated death
domain protein; cFLIP, caspase-8 homo-
logue FLICE-inhibitory protein; IKK, IjB
kinase; IjBa, inhibitor of kappa B; NFjB,
nuclear factor kappa B; RIP, receptor
interacting protein; TRADD, TNF receptor-
associated death domain; TRAF, TNF
receptor associate factor; TNF, tumor necro-

sis factor; TNFR1, tumor necrosis factor
receptor-1.
TNF receptor cross-talk P. J. W. Naude
´
et al.
890 FEBS Journal 278 (2011) 888–898 ª 2011 The Authors Journal compilation ª 2011 FEBS
to the nucleus and initiate transcription [43,44]. Poly-
ubiquitinated RIP1 can alternatively activate the IKK
complex via interaction of the TAK1 complex, consist-
ing of the TAK1 kinase and its associated proteins
TAK1-binding protein 1 ⁄ 2⁄ 3 (TAB 1, TAB 2 and
TAB 3). TAB 1–3 serve as the regulatory ubiquitin-
binding subunits and trigger the allosteric activation of
TAK1 [43,45], which in turn phosphorylates and acti-
vates IKK [46]. Activation of NF-jB allows it to
translocate to the nucleus and initiate transcription of
anti-apoptotic target genes, such as c-IAP1, c-IAP2,
caspase 8 homolog FLICE-inhibitory protein, TRAF1
and TRAF2 [47] (Fig. 1). Upon release from the
TNFR1 signaling complex, TRADD and RIP can also
associate with Fas-associated death domain protein
and caspase 8 forming a cytoplasmic complex (com-
plex II) which was not believed to be associated with
TNFR1, however, it was demonstrated by Schneider-
Brachert et al. [48] that TNR1 endocytosis and death-
inducing signaling complex formation are inseparable
events, which can then lead to caspase cascade activa-
tion, resulting in apoptosis [35,38,49]. Activation of the
classical NF-jB pathway (see Wajant and Scheurich
[42]) and RIP1 ubiquitination (see O’Donnell and Ting

[50]), which favorably occur during normal cellular
functioning, prevent TNF-induced apoptosis [51].
However, in circumstances of deficient accessibility of
c-IAP and FLICE-inhibitory protein, complex II trig-
gers caspase 8 activation and apoptotic cell death [52].
TNFR2 signaling pathway
Unlike TNFR1, TNFR2 does not possess a death
domain and induces a long-lasting NF-jB activation
[53], (Fig. 2). It has been shown that TNFR2 activa-
tion of NF-jB occurs independent of the TNFR1 sig-
naling pathway [54]. Indeed, it has been observed in
several cell lines that TNFR2 stimulation via mem-
brane-integrated TNF-a can activate the noncanonical
NF-jB pathway [55] as well as the canonical NF-jB
pathway [56]. TNFR2 is preferentially activated by
membrane-integrated TNF, whereas soluble TNF
binds TNFR2 but fails to properly stimulate TNFR2
signaling [29]. Trimerization of TNFR2 takes place
upon binding of TNF, which leads to the recruitment
of TRAF2 to the intracellular TRAF-binding motif
and consequently to indirect recruitment of the
TRAF2-associated proteins TRAF1, c-IAP1 and
c-IAP2, which already interact with TRAF2 in unstim-
ulated cells [53,57]. It has been shown that a
dominant-negative mutant of TRAF2 blocks TNFR2-
mediated NF-jB activation, whereas overexpression of
TRAF2 causes activation of NF-jB, suggesting that
TRAF2 plays a pivotal role in TNFR2-mediated NF-
jB activation [58]. In unstimulated cells, the TRAF2–
c-IAP1 ⁄ 2 complex interacts with a complex of TRAF3

and NF-jB-inducing kinase (NIK) resulting in
c-IAP1 ⁄ 2-mediated ubiquitination of NIK and the sub-
sequent proteosomal degradation of NIK. Recently,
it was demonstrated in several cell lines, including
primary immune cells, that only membrane-bound
TNF, and not soluble TNF trimers, stimulates the
noncanonical NF-jB pathway via TNFR2 stimulation
by deviation of the NIK degradation-inducing
TRAF2–c-IAP1 ⁄ 2 complex from the cytosol [55].
Thus, it was reported that TNFR2 activation results
in an accumulation of NIK. NIK is then able to
TNF-α
TRAF2
TRAF1
cIAP1/2
NIK
IKKα
α
P
P100
RelB
PI3K
PKB/Akt
P50 P65
Iκβ
P50 P65
RelA
P52
RelB
PTEN

Nucleus
TNFR2
Cellular membrane with membrane bound TNF-α
cIAP1/2
TRAF2
TRAF1
TRAF3
Fig. 2. TNFR2-mediated TNF signaling. cIAP cellular inhibitor of
apoptosis; IKK, IjB kinase; IjBa, inhibitor of kappa B; NIK, NFjB-
Inducing Kinase; PBK/Akt, protein kinase B/serine-threonine kinase;
PI3K, phosphoinositide 3-kinases; PTEN, phosphatase and tensin
homolog deleted on chromosome ten; NFjB, nuclear factor kappa
B; TRAF, TNF receptor associated factor; TNF, tumor necrosis fac-
tor; TNFR2, tumor necrosis factor receptor-2.
P. J. W. Naude
´
et al. TNF receptor cross-talk
FEBS Journal 278 (2011) 888–898 ª 2011 The Authors Journal compilation ª 2011 FEBS 891
stimulate IKKa. The NIK-activated IKKa in turn
phosphorylates the NF-jB precursor protein p100, thus
triggering its limited proteasomal proteolysis to p52,
which results in activation of p52-containing NF-jBs.
The noncanonical NF-jB activation is independent of
NF-jB essential modulator and IKKb [59]. TNFR2
can signal via the activation of Akt [60]. Upon exclusive
stimulation of TNFR2 in neurons lacking the TNFR1,
NF-jB was activated via the phosphatidylinositol
3-kinase–protein kinase B ⁄ serine-threonine kinase
pathway, whereas selective stimulation of TNFR1 in
TNFR2

) ⁄ )
neurons had no influence on this pathway
[56]. It has also been demonstrated that IKKa is the
prime target of this pathway, which then leads to IKKb
activation and subsequent IjBa phosphorylation [61]
and activation of cRel and p50 ⁄ p65, indicating that
NF-jB is activated via the canonical NF-jB pathway
[56]. In addition, coincubation of TNF with
a phosphatidylinositol 3-kinase inhibitor, LY294002, in
wild-type as well as in TNFR1
) ⁄ )
neurons (selective
TNFR2 activation) reduced IjBa phosphorylation[56],
thus indicating that the phosphatidylinositol 3-kinase-
protein kinase B ⁄ serine-threonine kinase pathway may
play a major role in TNFR2-mediated activation of
NF-jB. Furthermore, NF-jB activation via TNF leads
to a downregulation of the phosphatase and tensin
homolog deleted on chromosome ten protein, which is
a strong inhibitor of the phosphatidylinositol 3-kinase ⁄
Akt pathway. Thereby, this cascade may lead to an
autoregulatory loop, which could lead to a persistent
protein kinase B ⁄ serine-threonine kinase phosphory-
lation and sequentially NF-jB activation [62].
Involvement of TRAF1 and TRAF2 in
the cross-talk of TNFR1 and TNFR2
Contrary to the general belief that TNFR1 signaling
can cause apoptosis and that TNFR2 signaling path-
way primarily induces pro-survival, there is convinc-
ing evidence that exclusive TNFR2 stimulation can

trigger some cells to undergo apoptosis despite the
fact that TNFR2 does not contain a death domain
[63,64]. For this reason, it was speculated that some
form of receptor cross-talk might take place between
TNFR1 and TNFR2, especially via the involvement
of TRAFs, which has been confirmed by more recent
research. TRAFs are pivotal to TNF-a signaling and
are recruited to both TNFR1 and TNFR2 complexes
to commence cellular signaling [65]. TRAF2 plays a
crucial role in TNFR1-mediated activation of c-Jun
as well as NF-jB, which is essential for cellular
survival. These pathways can be inhibited by TNFR2-
mediated depletion of TRAF2 [66]. A few hours
prestimulation of TNFR2 with a TNFR2 agonist
causes depletion of endogenous TRAF2 [66]. c-IAP1
and c-IAP2, which were initially identified as compo-
nents of the TNFR2 signaling complex are also
recruited via TRAF2 into the TNFR1 signaling com-
plex. There is evidence that the TRAF2–c-IAP1 ⁄ 2
complex interferes with TNFR1-associated caspase 8
activation and apoptosis induction [47,67]. Stimula-
tion of TNFR2 leads to the recruitment of TRAF2
into a Triton X-100-insoluble compartment, and sub-
sequent ubiquitination and proteasomal degradation
via the TRAF2 associated c-IAP1 [66,68–70]. How-
ever, an important finding in that respect was that
TRAF1 interferes with this process and reduces
TNFR2-induced TRAF2 depletion by preserving
TRAF2 in the Triton X-100-soluble fraction. Further-
more, TRAF1 rescued TNFR1-induced NF-jB and

JNK activation of TNFR2-prestimulated TRAF1
transfected cells [71]. The important role of TRAF1
to induce NF-jB activation is possibly due to the
preservation of cytoplasmic TRAF2.
Contradictory results regarding the regulatory effects
of TRAF1 on NF-jB signaling have been reported by
in vitro studies, in which overexpression of TRAF1
caused an increase [72] but also an inhibition of NF-
jB activation [73]. In vivo, T cells from TRAF1-defi-
cient mice showed enhanced NF-jB activity and
increased IKKb activity [74], but dendritic cells from
TRAF1-deficient mice showed attenuated NF-jB sig-
naling [75]. TRAF molecules form homo- or hetero-
meric complexes. TRAF1 strongly interacts with
TRAF2 and the resulting complex plays important
roles in signaling function [2]. It has been shown that
the interaction of TRAF1 with TRAF2 represses
TNF-induced caspase 8 activation [47]. Transgenic
mice overexpressing TRAF1, for example, presented
reduced antigen-induced apoptosis of CD8
+
T cells
[76]. Conflicting results relating to TRAF1 might, at
least to some extent, be explained by the competence
of this molecule to manipulate the interaction of
TRAF2 with TRAF2-interacting receptors [66]. Inter-
estingly, in a study in which TRAF1-transfected cell
lines were used, it was shown that TRAF1 is corecruit-
ed together with TRAF2 to TNFR1 signaling complex
without affecting RIP modification or IKKa recruit-

ment [71]. Under these conditions, the amount of
TRAF2 recruitment to the TNFR1 complex was rela-
tively reduced. Thus, TRAF1 can act as a substitute
for TRAF2 in TNFR1 signaling as long as it is part of
a heteromeric complex with TRAF2 [71]. In addition,
TRAF2 recruitment to TNFR2 was also partially
reduced in these TRAF1-transfected cells. Moreover, it
can be speculated that heteromeric TRAF1–TRAF2
TNF receptor cross-talk P. J. W. Naude
´
et al.
892 FEBS Journal 278 (2011) 888–898 ª 2011 The Authors Journal compilation ª 2011 FEBS
complexes are more efficient to activate NF-jB than
homomeric TRAF2 complexes in TNFR2 signaling
[53,71]. This suggests that TRAF1 can substitute for
TRAF2 in TNFR1 as well as TNFR2 signaling com-
plex formation (Fig. 3).
Of note, TRAF1 is transcriptionally upregulated by
NF-jB [65,72], and degradation of TRAF2 is triggered
by TNFR2 signaling [65,77]. It can therefore be
expected that the duration of NF-jB activation can
shift the balance of the TRAF1⁄ TRAF2 ratio. There
might possibly be an alteration in the ratio of TRAF1
to TRAF2 that differs from normal cellular conditions
to inflammatory conditions. Costimulation of TNFR1
and TNFR2 can occur in the presence of cells express-
ing membrane TNF. In a study, it was observed that
although specific stimulation of either TNFR1 or
TNFR2 initially increased NF-jB, only TNFR2
induced cell proliferation of murine fibroblasts [78].

This can be explained by the signaling kinetics in the
activation of NF-jB differs considerably between
TNFR1 and TNFR2 upon stimulation via TNF-a.
After stimulation via TNFR1, NF-jB is activated for
 1–3 h, whereas TNFR2-mediated NF-jB activation
lasts for up to 24 h after stimulation [56]. Thus, in the
initial phase of TNF stimulation via its two receptors,
NF-jB activation via TNFR1 will take place before
TNFR2-induced depletion of TRAF2 has occurred.
TNFR1 is internalized rapidly into the cell and further
TNFR1 signaling will primarily depend on the activa-
tion of new receptor molecules emerging on the plasma
membrane. During stimulation of the newly formed
TNFR1, an environment in which TRAF2 has already
been degraded via TNFR2 stimulation will be present.
TNFR1–TNFR2 co-signaling becomes even more com-
plex because TNFR2-induced TRAF2 degradation
occurs only momentarily, which is then hampered by
TNFR1 TNFR2
TNF-α
TNF-α
Soluble
Membrane bound
Ub
Ub
Ub
RIP
TRAF2
P
P

NEMO
IKKα
IKKβ
NF-κB
TNF-α
TNF-α
Soluble
Membrane bound
TNFR1
TNFR2
TRADD
RIP
TRAF2/1
Ub
Ub
Ub
FADD
Caspase-8
Apoptosis
NF-κB target genes
TNF-α
TRAF1
TRAF2
TRAF1
cIAP1/2
TRAF1
TACE
cIAP1
ASK1
JNK

NF-κB
NF-κB
~ 30 min aŌer TNF-α sƟmulaƟon
> 2 hours aŌer TNF-α sƟmulaƟon
TRAaF 2
Fig. 3. Cellular signaling crosstalk between TNFR1 and TNFR2. ASK1, Apoptosis signal-regulating kinase 1; cIAP cellular inhibitor of apopto-
sis; FADD, Fas-associated death domain protein; IKK, IjB kinase; JNK, c-Jun N-terminal kinases; NFjB, nuclear factor-jB; RIP, receptor inter-
acting protein; TACE, TNF-alpha converting enzyme; TRADD, TNF receptor-associated death domain; TRAF, TNF receptor associate factor;
TNF, tumor necrosis factor; TNFR1, tumor necrosis factor receptor-1; TNFR2, tumor necrosis factor receptor-2.
P. J. W. Naude
´
et al. TNF receptor cross-talk
FEBS Journal 278 (2011) 888–898 ª 2011 The Authors Journal compilation ª 2011 FEBS 893
the upregulation of TRAF1 via earlier TNFR1 activa-
tion, thus diminishing cytoplasmic TRAF2 downregu-
lation. Moreover, induction of endogenous membrane
TNF might further promote TRAF1 to upregulate its
own production by enhancing TNFR2-induced NF-jB
signaling. This regulatory mechanism during long-term
TNF stimulation in TNFR1 and TNFR2 coexpressing
cells might explain the interaction between these two
receptors to prevent apoptosis by sustained NF-jB
activation [71].
Receptor cross-talk via regulation of
ASK1
Apoptosis signal-regulating kinase-1 (ASK1), a member
of the MAPK kinase kinase family, associates with
TRAF2 to induce the p38 and JNK activation upon
TNF stimulation [51,79]. During TNFR2 stimulation,
c-IAP1 and c-IAP2 are recruited to the receptor com-

plex. The c-IAP1 protein, in particular, induces TRAF2
degradation via ubiquitin protein ligase E3 activity [69].
This then can lead to an early termination of the TNF-
induced JNK pathway upon TNFR2 stimulation. Inter-
estingly, Zhao et al. showed that ASK1 is ubiquitinated
in TNFR2 expressing cell lines as well as in resting
B cells via E3 activity of c-IAP1, and that c-IAP1
) ⁄ )
B cells did not succeed to hinder TNF-induced MAP
kinase signaling [80]. In addition, it has also been sug-
gested that TNFR2, which is upregulated during inflam-
matory conditions, may control TNFR1 activation via
a feedback mechanism by reducing JNK activation.
Conclusion
The physiological and mechanistic involvement of
TNFR2 in the functioning of TNF has long been
underestimated for several reasons. Soluble TNF has
been used to study the effects of TNF, which predomi-
nantly stimulates TNFR1 and poorly activates
TNFR2. In addition, it was shown that only soluble
and not membrane-bound TNF triggers the expression
of alveolar monocyte chemoattractant protein-1 via
TNFR2 in alveolar epithelial cells, which append more
complexity to the signaling of TNFR2 [20]. TNFR2
also has restricted expression in specific cell types. It is
also sometimes difficult to measure detectable receptor
expression under normal physiological conditions.
Cross-talk between TNFR1 and TNFR2 occurs on
multiple levels. First, signaling kinetics differ signifi-
cantly between the two receptors. TNFR1-induced

NF-jB activation can occur in a matter of minutes
and normalize in a few hours, whereas TNFR2 can
take a few hours to promote NF-jB activation and
then can stay active for longer. Second, cross-talk
between the receptors can contribute to antagonistic as
well as agonistic effects of the two receptors on each
other’s signaling pathways. Third, the amount of
receptor expression can contribute to the complexity
of the cross-talk between receptors. This was shown
by Fontaine et al. [23], where receptor expression of
TNFR1 and TNFR2 were only detectable in neuronal
tissue after it was subjected to a stressful environment.
Cross-talk of the receptors can play a pivotal role
in physiological processes of many entirely different
aspects in the living organism. It has been shown that
TNFR1 is required for hepatocyte DNA synthesis
and liver regeneration [81], however, in an acute
hepatocyte toxicity model TNFR1 plays a detrimental
role in liver destruction [82], possibly due to upregu-
lation of TNFR1. Fascinatingly, transgenic mice
expressing noncleavable transmembrane TNF in endo-
thelial cells were protected against Concanava-
lin A-induced liver failure [83]. This protective effect can
be attributed to the increased binding affinity of mem-
brane-bound TNF to TNFR2. The same effect on tissue
destruction and protection was observed in brain tissue
[23]. Furthermore, it has been reported that TNFR1
and TNFR2 in concert are involved in cognitive behav-
iors under normal physiological conditions [84].
TNF has a diversity of functions which is not

solely restricted to either TNFR1 or TNFR2 signal-
ing, but rather is dependent on the temporal dynam-
ics of cross-talk between TNFR1 and TNFR2
according to the physiological conditions in which it
occurs.
Acknowlegements
This work was supported by grants from the Interna-
tional Foundation for Alzheimer Research (ISAO),
grant no. 06511, the Gratama Foundation and the
EU-grant FP6 NeuroproMiSe LSHM-CT-2005-018637
to ULME and a stipend from the School of Beha-
vioural and Cognitive Neuroscience for PJWN.
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