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: U.L.M.Eisel@rug.nl (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]. 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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. 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. 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