Arthritis & Rheumatism DOI 10.1002/art.38753
Editorial
Balancing TNFR1 and TNFR2 Jointly for Joint Inflammation
Bharat B. Aggarwal, PhD Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030
Running title: Role of TNFR1 and TNFR2 in RA
Invited Review for Arthritis & Rheumatology
Grant support: This work was supported by a grant from Malaysian Palm Oil Board.
Corresponding author: Bharat B. Aggarwal, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. Phone: 713-794-1817; Email: [email protected]
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/art.38753 © 2014 American College of Rheumatology Received: May 21, 2014; Revised: Jun 09, 2014; Accepted: Jun 17, 2014
Arthritis & Rheumatology
Human tumor necrosis factor (TNF)-α is a 17-kDa protein that was first isolated in 1985 from human macrophage cell line HL-60 as an anticancer agent (1, 2). Since then, this cytokine has been shown to be produced by a wide variety of both immune and non-immune cells (3). Extensive research over the past three decades has demonstrated that TNF-α is a highly pleiotropic cytokine that mediates apoptotic, proliferative, proinflammatory, immunomodulatory, angiogenic, neurologic, metabolic, antifungal, antiviral, and antibacterial effects (4). How one cytokine can mediate all these effects at the molecular level is still not fully understood. TNF-α has been shown to bind to two distinct receptors, TNFR1 and TNFR2, with a molecular mass of 60 kDa (also referred as 55 kDa) and 80 kDa (or 75 kDa), respectively. Whereas TNFR1 is expressed on the cell surface of virtually all cell types in the body, TNFR2 is expressed only on the surface of endothelial cells, cardiac myocytes, and immune system cells of various types. These two receptors have been shown to bind to TNF-α with almost equal affinity. TNFR1 differs from TNFR2 in that the cytoplasmic domain of R1 exhibits a specific death domain (DD) that is lacking in the R2 receptor. On activation by the ligand TNF-α, through the DD domain, TNFR1 recruits TRADD, TRAF2, FADD, and FLICE, which mediate most of the signaling pathways through the activation of various kinases, and caspases leading to cell death and inflammatory response (see Fig. 1). How TNFR2, which lacks the DD, mediates cell signaling, however, is less well understood. Also not well understood is why there are two different receptors for TNF-α and why some cell types express these receptors whereas others do not. Overexpression of TNFR2 has been shown to induce apoptosis and to activate NF-kB (5). Using TNFR1- and TNFR2deficient mice, it has been shown that TNFR1 mediates the inflammatory response whereas TNFR2 activates antiinflammatory responses (6, 7). TNF-α is the most potent activator of transcription factor NF-κB, which controls the majority of proinflammatory signals linked to this ligand. Therefore, TNF-α blockers such as infliximab (antibody against TNF-α), adalimumab (humanized antibody against TNF-α), and etanercept (soluble form of TNFR2) have been approved by the FDA for proinflammatory diseases such as inflammatory bowel disease, psoriasis, and rheumatoid arthritis (see 4). Because all of the currently approved TNF-α blockers have numerous adverse effects, they all exhibit a “black label” warning. Thus TNF-α blockers that have minimal adverse effects are highly desirable. A large number of cell types of the immune system are known to play a role in the pathogenesis of arthritis, including T helper (Th)1 cells that secrete IFN-γ; Th2 cells that secrete IL-4 and IL-5; Th17 cells that secrete IL-17; and T effector (Teff) cells that secrete TNF-α; and T regulatory cells (Treg) (see Fig. 2). In addition, TNF-α, secreted by macrophages and dendritic cells, plays a major role in arthritis. The cytokine IFN-γ has been shown to upregulate TNF receptors (8) whereas IL-4 has been shown to Interleukin-4 down-regulates both forms of TNFR and receptor-mediated proinflammatory signals (9). Teff cells mediate
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Page 2 of 8
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Arthritis & Rheumatology
autoimmunity, whereas CD4+CD25+Foxp3+ Tregs have been shown to play a major role in the prevention of autoimmune diseases. The expression of Foxp3 by Treg is known to be upregulated by infliximab. CD4+ Teff activation can enhance the expansion and suppressive activity of Treg (10). Further studies indicated that these effects of Teff on Treg are mediated through the production of TNF-α and involve TNFR2 expression on Treg. The T regulatory cells are also known to be regulated by Th17 cells through the TNF-α-TNFR2 pathway. The studies described by McCann et al. in this issue of Arthritis and Rheumatism provide evidence to support the thesis that instead of targeting TNF-α for blockade, it may be better to target TNFR1 to inhibit inflammation and to promote CD4+, CD25+, and FoxP3+ Treg activity (11). These studies are based on reports that suggest that TNFR1 mediates a proinflammatory role, whereas TNFR2 may exhibit an immunosuppressive role through promotion of Treg cells (12). The authors’ studies are based on the collagen-induced arthritis (CIA) mouse model for rheumatoid arthritis (RA). The authors used specific antibodies that either block TNFR1 or block both TNFR1 and TNFR2. With use of this model, the authors demonstrate that: 1. Selective TNFR1 blockade with anti-TNFR1 ameliorates CIA. 2. Levels of circulating T-cell–derived cytokines are elevated in CIA after blockade of TNFR1/TNFR2 but not after blockade of TNFR1 alone. 3. The numbers of TREG are reduced after blockade of TNFR1/TNFR2 but not after blockage of TNFR1 alone. 4. Selective blockade of TNFR1 enables TREG to suppress IL-17 production. 5. Genetic deletion of TNFR1 further increases the ability of TREG to suppress T-cell proliferation and cytokine production. 6. Gene expression of TNFR2 and FoxP3 are tightly regulated in arthritic paw of CIA mice. On the basis of these studies, the authors concluded that blocking TNFR1 may be superior to blocking TNF-α because TNFR2 mediates an immunoregulatory role that has immunosuppressive implications and thus should be spared. These studies, however, disagree with a previous report that showed that injection of TNF-α into TNFR1-KO mice during the early induction phase enhanced the development of arthritis but inhibited this condition when administered during the late progression phase (13). These results suggest that TNFR2 alone can transduce opposing signals, and the activation of TNFR2 by TNF is also involved in the development of CIA. In a murine model of erosive arthritis, Bluml et al. (2010) reported that expression of TNFR2 on hematopoietic cells mediates an antiinflammatory role and prevents bone destruction (14). In animals with collagen-induced arthritis, the activity of Treg is also counter-regulated by IFN-γ
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Arthritis & Rheumatology
produced by Th1 cells, which may be in part due to upregulation of TNFR by this cytokine. As in the CIA model described here, the two types of TNF receptors have been shown to mediate opposite effects in other systems as well. For instance, TNFα–induced cardiomyopathy has been shown to be differentially regulated by TNFR1 and TNFR2 for cardiac dysfunction and for cardiac survival, respectively (15), with TNFR1 linked to heart failure and TNFR2 found to be cardioprotective. Overall, these studies clearly indicate that TNF-α is a highly pleiotropic molecule and that two different receptors for this cytokine mediate different signals. How these signals are mediated is more evident for TNFR1 than for TNFR2. Because proinflammatory signals are mediated through TNFR1, targeting this receptor for blockade is preferable to targeting TNFR2. The latter, however, may exhibit desirable effects in some cells and undesirable effects in other cell types or organs. Thus, the role of the two receptors is highly context-dependent.
References: 1. Aggarwal, B.B., W.J. Kohr, P.E. Hass, B. Moffat, S.A. Spencer, W.J. Henzel, T.S. Bringman, G.E. Nedwin, D.V. Goeddel, R.N. Harkins, Human tumor necrosis factor: Production, purification and characterization. Journal of Biological Chemistry, 1985, 260(4):2345-2354. 2. Pennica, D., G.E. Nedwin, J.F. Hayflick, P.H. Seeburg, M.A. Palladino, W.J. Kohr, B.B. Aggarwal and D.V. Goeddel, Human tumor necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature, 1984, 312(5996):724-729. 3. Aggarwal, B.B., Signaling pathways of the TNF superfamily: a double-edged sword. Nature Review Immunology, 2003, 3(9):745-756. 4. Aggarwal BB, Gupta SC, Kim JH. Historical perspectives on tumor necrosis factor and its superfamily: twenty-five years later, a golden journey. Blood. 2012; 119 (3):651-665. 5. Haridas, V., B.G. Darnay, K. Natarajan, R. Heller and B.B. Aggarwal, Overexpression of the p80 TNF receptor leads to TNF-dependent apoptosis, NFB activation and c-Jun kinase activation. Journal of Immunology, 1998, 160(7):3152-3162. 6. Peschon JJ, Torrance DS, Stocking KL, Glaccum MB, Otten C, Willis CR, Charrier K, Morrissey PJ, Ware CB, Mohler KM. TNF receptor-deficient mice reveal divergent roles for p55 and p75 in several models of inflammation. J Immunol. 1998 Jan 15;160(2):943-952.
John Wiley & Sons
Page 4 of 8
Page 5 of 8
Arthritis & Rheumatology
7. Blüml S, Scheinecker C, Smolen JS, Redlich K. Targeting TNF receptors in rheumatoid arthritis. Int Immunol. 2012 May; 24(5):275-281. 8. Aggarwal BB, Eessalu TE, Hass PE. Characterization of receptors for human tumour necrosis factor and their regulation by gamma-interferon. Nature. 1985 Dec 19-1986 Jan 1;318(6047):665-7. PubMed PMID: 3001529. 9. Manna SK, Aggarwal BB. Interleukin-4 down-regulates both forms of tumor necrosis factor receptor and receptor-mediated apoptosis, NF-kappaB, AP-1, and c-Jun N-terminal kinase. Comparison with interleukin-13. J Biol Chem. 1998 Dec 11;273(50):33333-41. PubMed PMID: 9837907. 10. Grinberg-Bleyer Y, Saadoun D, Baeyens A, Billiard F, Goldstein JD, Grégoire S, Martin GH, Elhage R, Derian N, Carpentier W, Marodon G, Klatzmann D, Piaggio E, Salomon BL. Pathogenic T cells have a paradoxical protective effect in murine autoimmune diabetes by boosting Tregs. J Clin Invest. 2010 Dec;120(12):4558-68. doi: 10.1172/JCI42945. Epub 2010 Nov 22. PubMed PMID: 21099113; PubMed Central PMCID: PMC2993590. 11. McCann, F; Perocheau, D; Ruspi, G; Blazek, K; Davies, M; Stoop, A; Dean, J; Feldmann, M; and Williams, R; TNFR1 blockade is anti-inflammatory and reveals an immunoregulatory role for TNFR2. Arthritis & Rheumatology (this issue). 12. Chen X, Bäumel M, Männel DN, Howard OM, Oppenheim JJ. Interaction of TNF with TNF receptor type 2 promotes expansion and function of mouse CD4+CD25+ T regulatory cells. J Immunol. 2007 Jul 1;179(1):154-161. 13. Tada Y, Ho A, Koarada S, Morito F, Ushiyama O, Suzuki N, Kikuchi Y, Ohta A, Mak TW, Nagasawa K. Collagen-induced arthritis in TNF receptor-1-deficient mice: TNF receptor-2 can modulate arthritis in the absence of TNF receptor-1. Clin Immunol. 2001 Jun;99(3):325-333. 14. Blüml S, Binder NB, Niederreiter B, Polzer K, Hayer S, Tauber S, Schett G, Scheinecker C, Kollias G, Selzer E, Bilban M, Smolen JS, Superti-Furga G, Redlich K. Antiinflammatory effects of tumor necrosis factor on hematopoietic cells in a murine model of erosive arthritis. Arthritis Rheum. 2010 Jun;62(6):1608-19. doi: 10.1002/art.27399. PubMed PMID: 20155834. 15. Higuchi Y, McTiernan CF, Frye CB, McGowan BS, Chan TO, Feldman AM. Tumor necrosis factor receptors 1 and 2 differentially regulate survival, cardiac dysfunction, and remodeling in transgenic mice with tumor necrosis factor-alphainduced cardiomyopathy. Circulation. 2004 Apr 20;109(15):1892-1897.
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Arthritis & Rheumatology
Figure Legends: Figure 1: A diagram depicting similarities and differences in TNF-α signaling through TNFR1 and TNFR2. The cytoplasmic domain of TNFR1 has been shown to mediate apoptosis through sequential recruitment of TRADD-FADD-FLICE by the death domain located within the cytoplasmic domain; and recruitment of TRADD-TRAF2 leads to activation of NF-kB which then mediates inflammation linked to wide variety of diseases including Arthritis and heart failure. TNFR2 in contrast has been shown to recruit TRAF2 through TRAF1; and plays an immunoregulatory, angiogenesis and cardioprotective role. Figure 2: Role of T cells and other immune cells in the pathogenesis of rheumatoid arthritis. The role of T helper (Th)1, Th17 and Teff cells has been closely linked to the autoimmunity. Wide variety of cells (Teff, Th1, macrophages and dendritic cells) produce TNF-α which interacts with TNFR2 leading to proliferation of Treg cells, thus downmodulating autoimmunity.
John Wiley & Sons
Page 6 of 8
Page 7 of 8
Arthritis & Rheumatology
TNF- α
TNFR1
TNFR2
Cell membrane
TRADD
TRADD TRAF1
D
TRAF2
TRAF2
FLICE
NF-kappaB Inflammation
poptosis
e.g; Arthritis Heart Failure
Immunoregulation Antiinflammatory Suppress bone loss Promote Treg function Ischemia-induced neovascularization John Wiley & Sons Tumor angiogenesis Cardioprotective
??
Arthritis & Rheumatology
Dendritic cells
Macrophages
Page 8 of 8
Th1 cells
Treg
(T regulatory cells)
CTLA-4+ CD4+; CD25+ FoxP3+
Teff
TNFR2
Autoimmunity
TNF- α
John Wiley & Sons
(T effector cells)
CD4+
Th1
Th17
Autoimmunity
Editorial
Balancing TNFR1 and TNFR2 Jointly for Joint Inflammation
Bharat B. Aggarwal, PhD Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030
Running title: Role of TNFR1 and TNFR2 in RA
Invited Review for Arthritis & Rheumatology
Grant support: This work was supported by a grant from Malaysian Palm Oil Board.
Corresponding author: Bharat B. Aggarwal, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. Phone: 713-794-1817; Email: [email protected]
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/art.38753 © 2014 American College of Rheumatology Received: May 21, 2014; Revised: Jun 09, 2014; Accepted: Jun 17, 2014
Arthritis & Rheumatology
Human tumor necrosis factor (TNF)-α is a 17-kDa protein that was first isolated in 1985 from human macrophage cell line HL-60 as an anticancer agent (1, 2). Since then, this cytokine has been shown to be produced by a wide variety of both immune and non-immune cells (3). Extensive research over the past three decades has demonstrated that TNF-α is a highly pleiotropic cytokine that mediates apoptotic, proliferative, proinflammatory, immunomodulatory, angiogenic, neurologic, metabolic, antifungal, antiviral, and antibacterial effects (4). How one cytokine can mediate all these effects at the molecular level is still not fully understood. TNF-α has been shown to bind to two distinct receptors, TNFR1 and TNFR2, with a molecular mass of 60 kDa (also referred as 55 kDa) and 80 kDa (or 75 kDa), respectively. Whereas TNFR1 is expressed on the cell surface of virtually all cell types in the body, TNFR2 is expressed only on the surface of endothelial cells, cardiac myocytes, and immune system cells of various types. These two receptors have been shown to bind to TNF-α with almost equal affinity. TNFR1 differs from TNFR2 in that the cytoplasmic domain of R1 exhibits a specific death domain (DD) that is lacking in the R2 receptor. On activation by the ligand TNF-α, through the DD domain, TNFR1 recruits TRADD, TRAF2, FADD, and FLICE, which mediate most of the signaling pathways through the activation of various kinases, and caspases leading to cell death and inflammatory response (see Fig. 1). How TNFR2, which lacks the DD, mediates cell signaling, however, is less well understood. Also not well understood is why there are two different receptors for TNF-α and why some cell types express these receptors whereas others do not. Overexpression of TNFR2 has been shown to induce apoptosis and to activate NF-kB (5). Using TNFR1- and TNFR2deficient mice, it has been shown that TNFR1 mediates the inflammatory response whereas TNFR2 activates antiinflammatory responses (6, 7). TNF-α is the most potent activator of transcription factor NF-κB, which controls the majority of proinflammatory signals linked to this ligand. Therefore, TNF-α blockers such as infliximab (antibody against TNF-α), adalimumab (humanized antibody against TNF-α), and etanercept (soluble form of TNFR2) have been approved by the FDA for proinflammatory diseases such as inflammatory bowel disease, psoriasis, and rheumatoid arthritis (see 4). Because all of the currently approved TNF-α blockers have numerous adverse effects, they all exhibit a “black label” warning. Thus TNF-α blockers that have minimal adverse effects are highly desirable. A large number of cell types of the immune system are known to play a role in the pathogenesis of arthritis, including T helper (Th)1 cells that secrete IFN-γ; Th2 cells that secrete IL-4 and IL-5; Th17 cells that secrete IL-17; and T effector (Teff) cells that secrete TNF-α; and T regulatory cells (Treg) (see Fig. 2). In addition, TNF-α, secreted by macrophages and dendritic cells, plays a major role in arthritis. The cytokine IFN-γ has been shown to upregulate TNF receptors (8) whereas IL-4 has been shown to Interleukin-4 down-regulates both forms of TNFR and receptor-mediated proinflammatory signals (9). Teff cells mediate
John Wiley & Sons
Page 2 of 8
Page 3 of 8
Arthritis & Rheumatology
autoimmunity, whereas CD4+CD25+Foxp3+ Tregs have been shown to play a major role in the prevention of autoimmune diseases. The expression of Foxp3 by Treg is known to be upregulated by infliximab. CD4+ Teff activation can enhance the expansion and suppressive activity of Treg (10). Further studies indicated that these effects of Teff on Treg are mediated through the production of TNF-α and involve TNFR2 expression on Treg. The T regulatory cells are also known to be regulated by Th17 cells through the TNF-α-TNFR2 pathway. The studies described by McCann et al. in this issue of Arthritis and Rheumatism provide evidence to support the thesis that instead of targeting TNF-α for blockade, it may be better to target TNFR1 to inhibit inflammation and to promote CD4+, CD25+, and FoxP3+ Treg activity (11). These studies are based on reports that suggest that TNFR1 mediates a proinflammatory role, whereas TNFR2 may exhibit an immunosuppressive role through promotion of Treg cells (12). The authors’ studies are based on the collagen-induced arthritis (CIA) mouse model for rheumatoid arthritis (RA). The authors used specific antibodies that either block TNFR1 or block both TNFR1 and TNFR2. With use of this model, the authors demonstrate that: 1. Selective TNFR1 blockade with anti-TNFR1 ameliorates CIA. 2. Levels of circulating T-cell–derived cytokines are elevated in CIA after blockade of TNFR1/TNFR2 but not after blockade of TNFR1 alone. 3. The numbers of TREG are reduced after blockade of TNFR1/TNFR2 but not after blockage of TNFR1 alone. 4. Selective blockade of TNFR1 enables TREG to suppress IL-17 production. 5. Genetic deletion of TNFR1 further increases the ability of TREG to suppress T-cell proliferation and cytokine production. 6. Gene expression of TNFR2 and FoxP3 are tightly regulated in arthritic paw of CIA mice. On the basis of these studies, the authors concluded that blocking TNFR1 may be superior to blocking TNF-α because TNFR2 mediates an immunoregulatory role that has immunosuppressive implications and thus should be spared. These studies, however, disagree with a previous report that showed that injection of TNF-α into TNFR1-KO mice during the early induction phase enhanced the development of arthritis but inhibited this condition when administered during the late progression phase (13). These results suggest that TNFR2 alone can transduce opposing signals, and the activation of TNFR2 by TNF is also involved in the development of CIA. In a murine model of erosive arthritis, Bluml et al. (2010) reported that expression of TNFR2 on hematopoietic cells mediates an antiinflammatory role and prevents bone destruction (14). In animals with collagen-induced arthritis, the activity of Treg is also counter-regulated by IFN-γ
John Wiley & Sons
Arthritis & Rheumatology
produced by Th1 cells, which may be in part due to upregulation of TNFR by this cytokine. As in the CIA model described here, the two types of TNF receptors have been shown to mediate opposite effects in other systems as well. For instance, TNFα–induced cardiomyopathy has been shown to be differentially regulated by TNFR1 and TNFR2 for cardiac dysfunction and for cardiac survival, respectively (15), with TNFR1 linked to heart failure and TNFR2 found to be cardioprotective. Overall, these studies clearly indicate that TNF-α is a highly pleiotropic molecule and that two different receptors for this cytokine mediate different signals. How these signals are mediated is more evident for TNFR1 than for TNFR2. Because proinflammatory signals are mediated through TNFR1, targeting this receptor for blockade is preferable to targeting TNFR2. The latter, however, may exhibit desirable effects in some cells and undesirable effects in other cell types or organs. Thus, the role of the two receptors is highly context-dependent.
References: 1. Aggarwal, B.B., W.J. Kohr, P.E. Hass, B. Moffat, S.A. Spencer, W.J. Henzel, T.S. Bringman, G.E. Nedwin, D.V. Goeddel, R.N. Harkins, Human tumor necrosis factor: Production, purification and characterization. Journal of Biological Chemistry, 1985, 260(4):2345-2354. 2. Pennica, D., G.E. Nedwin, J.F. Hayflick, P.H. Seeburg, M.A. Palladino, W.J. Kohr, B.B. Aggarwal and D.V. Goeddel, Human tumor necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature, 1984, 312(5996):724-729. 3. Aggarwal, B.B., Signaling pathways of the TNF superfamily: a double-edged sword. Nature Review Immunology, 2003, 3(9):745-756. 4. Aggarwal BB, Gupta SC, Kim JH. Historical perspectives on tumor necrosis factor and its superfamily: twenty-five years later, a golden journey. Blood. 2012; 119 (3):651-665. 5. Haridas, V., B.G. Darnay, K. Natarajan, R. Heller and B.B. Aggarwal, Overexpression of the p80 TNF receptor leads to TNF-dependent apoptosis, NFB activation and c-Jun kinase activation. Journal of Immunology, 1998, 160(7):3152-3162. 6. Peschon JJ, Torrance DS, Stocking KL, Glaccum MB, Otten C, Willis CR, Charrier K, Morrissey PJ, Ware CB, Mohler KM. TNF receptor-deficient mice reveal divergent roles for p55 and p75 in several models of inflammation. J Immunol. 1998 Jan 15;160(2):943-952.
John Wiley & Sons
Page 4 of 8
Page 5 of 8
Arthritis & Rheumatology
7. Blüml S, Scheinecker C, Smolen JS, Redlich K. Targeting TNF receptors in rheumatoid arthritis. Int Immunol. 2012 May; 24(5):275-281. 8. Aggarwal BB, Eessalu TE, Hass PE. Characterization of receptors for human tumour necrosis factor and their regulation by gamma-interferon. Nature. 1985 Dec 19-1986 Jan 1;318(6047):665-7. PubMed PMID: 3001529. 9. Manna SK, Aggarwal BB. Interleukin-4 down-regulates both forms of tumor necrosis factor receptor and receptor-mediated apoptosis, NF-kappaB, AP-1, and c-Jun N-terminal kinase. Comparison with interleukin-13. J Biol Chem. 1998 Dec 11;273(50):33333-41. PubMed PMID: 9837907. 10. Grinberg-Bleyer Y, Saadoun D, Baeyens A, Billiard F, Goldstein JD, Grégoire S, Martin GH, Elhage R, Derian N, Carpentier W, Marodon G, Klatzmann D, Piaggio E, Salomon BL. Pathogenic T cells have a paradoxical protective effect in murine autoimmune diabetes by boosting Tregs. J Clin Invest. 2010 Dec;120(12):4558-68. doi: 10.1172/JCI42945. Epub 2010 Nov 22. PubMed PMID: 21099113; PubMed Central PMCID: PMC2993590. 11. McCann, F; Perocheau, D; Ruspi, G; Blazek, K; Davies, M; Stoop, A; Dean, J; Feldmann, M; and Williams, R; TNFR1 blockade is anti-inflammatory and reveals an immunoregulatory role for TNFR2. Arthritis & Rheumatology (this issue). 12. Chen X, Bäumel M, Männel DN, Howard OM, Oppenheim JJ. Interaction of TNF with TNF receptor type 2 promotes expansion and function of mouse CD4+CD25+ T regulatory cells. J Immunol. 2007 Jul 1;179(1):154-161. 13. Tada Y, Ho A, Koarada S, Morito F, Ushiyama O, Suzuki N, Kikuchi Y, Ohta A, Mak TW, Nagasawa K. Collagen-induced arthritis in TNF receptor-1-deficient mice: TNF receptor-2 can modulate arthritis in the absence of TNF receptor-1. Clin Immunol. 2001 Jun;99(3):325-333. 14. Blüml S, Binder NB, Niederreiter B, Polzer K, Hayer S, Tauber S, Schett G, Scheinecker C, Kollias G, Selzer E, Bilban M, Smolen JS, Superti-Furga G, Redlich K. Antiinflammatory effects of tumor necrosis factor on hematopoietic cells in a murine model of erosive arthritis. Arthritis Rheum. 2010 Jun;62(6):1608-19. doi: 10.1002/art.27399. PubMed PMID: 20155834. 15. Higuchi Y, McTiernan CF, Frye CB, McGowan BS, Chan TO, Feldman AM. Tumor necrosis factor receptors 1 and 2 differentially regulate survival, cardiac dysfunction, and remodeling in transgenic mice with tumor necrosis factor-alphainduced cardiomyopathy. Circulation. 2004 Apr 20;109(15):1892-1897.
John Wiley & Sons
Arthritis & Rheumatology
Figure Legends: Figure 1: A diagram depicting similarities and differences in TNF-α signaling through TNFR1 and TNFR2. The cytoplasmic domain of TNFR1 has been shown to mediate apoptosis through sequential recruitment of TRADD-FADD-FLICE by the death domain located within the cytoplasmic domain; and recruitment of TRADD-TRAF2 leads to activation of NF-kB which then mediates inflammation linked to wide variety of diseases including Arthritis and heart failure. TNFR2 in contrast has been shown to recruit TRAF2 through TRAF1; and plays an immunoregulatory, angiogenesis and cardioprotective role. Figure 2: Role of T cells and other immune cells in the pathogenesis of rheumatoid arthritis. The role of T helper (Th)1, Th17 and Teff cells has been closely linked to the autoimmunity. Wide variety of cells (Teff, Th1, macrophages and dendritic cells) produce TNF-α which interacts with TNFR2 leading to proliferation of Treg cells, thus downmodulating autoimmunity.
John Wiley & Sons
Page 6 of 8
Page 7 of 8
Arthritis & Rheumatology
TNF- α
TNFR1
TNFR2
Cell membrane
TRADD
TRADD TRAF1
D
TRAF2
TRAF2
FLICE
NF-kappaB Inflammation
poptosis
e.g; Arthritis Heart Failure
Immunoregulation Antiinflammatory Suppress bone loss Promote Treg function Ischemia-induced neovascularization John Wiley & Sons Tumor angiogenesis Cardioprotective
??
Arthritis & Rheumatology
Dendritic cells
Macrophages
Page 8 of 8
Th1 cells
Treg
(T regulatory cells)
CTLA-4+ CD4+; CD25+ FoxP3+
Teff
TNFR2
Autoimmunity
TNF- α
John Wiley & Sons
(T effector cells)
CD4+
Th1
Th17
Autoimmunity
