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• W2062462227 abstract "The members of the tumor necrosis factor (TNF) family play pivotal roles in the regulation of the immune system. Here we describe a new ligand in this family, designated TWEAK. The mouse and human versions of this protein are unusually conserved with 93% amino acid identity in the receptor binding domain. The protein was efficiently secreted from cells indicating that, like TNF, TWEAK may have the long range effects of a secreted cytokine. TWEAK transcripts were abundant and found in many tissues, suggesting that TWEAK and TRAIL belong to a new group of widely expressed ligands. Like many members of the TNF family, TWEAK was able to induce interleukin-8 synthesis in a number of cell lines. The human adenocarcinoma cell line, HT29, underwent apoptosis in the presence of both TWEAK and interferon-γ. Thus, TWEAK resembles many other TNF ligands in the capacity to induce cell death; however, the fact that TWEAK-sensitive cells are relatively rare suggests that TWEAK along with lymphotoxins α/β and possibly CD30L trigger death via a weaker, nondeath domain-dependent mechanism. The members of the tumor necrosis factor (TNF) family play pivotal roles in the regulation of the immune system. Here we describe a new ligand in this family, designated TWEAK. The mouse and human versions of this protein are unusually conserved with 93% amino acid identity in the receptor binding domain. The protein was efficiently secreted from cells indicating that, like TNF, TWEAK may have the long range effects of a secreted cytokine. TWEAK transcripts were abundant and found in many tissues, suggesting that TWEAK and TRAIL belong to a new group of widely expressed ligands. Like many members of the TNF family, TWEAK was able to induce interleukin-8 synthesis in a number of cell lines. The human adenocarcinoma cell line, HT29, underwent apoptosis in the presence of both TWEAK and interferon-γ. Thus, TWEAK resembles many other TNF ligands in the capacity to induce cell death; however, the fact that TWEAK-sensitive cells are relatively rare suggests that TWEAK along with lymphotoxins α/β and possibly CD30L trigger death via a weaker, nondeath domain-dependent mechanism. Cytokines of the TNF 1The abbreviations used are: TNF, tumor necrosis factor; IL, interleukin; TNF-R, TNF receptor; NGF, nerve growth factor; RACE, rapid amplification of cDNA ends; LT, lymphotoxin; PCR, polymerase chain reaction; bp, base pair(s); kb, kilobase pair(s); EST, expressed sequence tag; PAGE, polyacrylamide gel electrophoresis; PBS, phosphate-buffered saline; FACS, fluorescence-activated cell sorting; IFN, interferon; EBNA, Epstein-Barr virus nuclear antigen; DAPI, 4′,6-diamidino-2-phenylindole. 1The abbreviations used are: TNF, tumor necrosis factor; IL, interleukin; TNF-R, TNF receptor; NGF, nerve growth factor; RACE, rapid amplification of cDNA ends; LT, lymphotoxin; PCR, polymerase chain reaction; bp, base pair(s); kb, kilobase pair(s); EST, expressed sequence tag; PAGE, polyacrylamide gel electrophoresis; PBS, phosphate-buffered saline; FACS, fluorescence-activated cell sorting; IFN, interferon; EBNA, Epstein-Barr virus nuclear antigen; DAPI, 4′,6-diamidino-2-phenylindole.family are mediators of host defense and immune regulation. Members of this family act either locally through direct cell-to-cell contact or as secreted proteins capable of diffusing to more distant targets. These proteins are synthesized as type II membrane proteins with the extracellular C-terminal region mediating binding to the receptors of the TNF receptor (TNF-R) family (1Smith C.A. Farrah T. Goodwin R.G. Cell. 1994; 76: 959-962Abstract Full Text PDF PubMed Scopus (1831) Google Scholar). The TNF family of ligands and receptors comprises at least 14 unique signaling pathways including TNF, lymphotoxins (LT), Fas, CD27, CD30, CD40, 4–1BB, OX-40, TRAMP (also DR3, WSL-1, Apo-3), CAR-1, TRAIL, GITR, HVEM, osteoprotegerin, and NGF (2Chinnaiyan A.M. O'Rourke K. Yu G.-L. Lyons R.H. Garg M. Duan D.R. Xing L. Gentz R. Ni J. Dixit V.M. Science. 1996; 274: 990-992Crossref PubMed Scopus (529) Google Scholar, 3Bodmer J.-L. Burns K. Schneider P. Hofmann K. Steiner V. Thome M. Bornand T. Hahne M. Schroeter M. Becker K. Wilson A. French L.E. Browning J.L. MacDonald H.R. Tschopp J. Immunity. 1997; 6: 79-88Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar, 4Kitson J. Raven T. Jiang Y.-P. Goeddel D.V. Giles K.M. Pun K.-T. Grinham C.J. Brown R. Farrow S.N. Nature. 1996; 384: 372-375Crossref PubMed Scopus (293) Google Scholar, 5Wiley S.R. Schooley K. Smolak P.J. Din W.S. Huang C.-P. Nicholl J.K. Sutherland G.R. Smith T.D. Rauch C. Smith C.A. Goodwin R.G. Immunity. 1995; 3: 673-682Abstract Full Text PDF PubMed Scopus (2636) Google Scholar, 6Montgomery R.I. Warner M.S. Lum B.J. Spear P.G. Cell. 1996; 87: 427-436Abstract Full Text Full Text PDF PubMed Scopus (998) Google Scholar, 7Brojatsch J. Naughton J. Rolls M.M. Zingler K. Young J.A.T. Cell. 1996; 87: 845-855Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar, 8Pan G. O'Rourke K. Chinnaiyan A.M. Gentz R. Ebner R. Ni J. Dixit V.M. Science. 1997; 276: 111-113Crossref PubMed Scopus (1546) Google Scholar, 9Pan G. Ni J. Wei Y.-F. Yu G.-L. Gentz R. Dixit V.M. Science. 1997; 277: 815-818Crossref PubMed Scopus (1373) Google Scholar, 10Sheridan J.P. Marsters S.A. Pitti R.M. Gurney A. Skubatch M. Baldwin D. Ramakrishnan L. Gray C.L. Baker K. Wood W.I. Goddard A.D. Godowski P. Ashkenazi A. Science. 1997; 277: 818-821Crossref PubMed Scopus (1519) Google Scholar, 11Nocentini G. Giunchi L. Ronchetti S. Krausz L.T. Bartoli A. Moraca R. Migliorati G. Riccardi C. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 6216-6221Crossref PubMed Scopus (365) Google Scholar, 12Simonet W.S. Lacey D.L. Dunstan C.R. Kelley M. Chang M.-S. Luethy R. Nguyen H.Q. Wooden S. Bennett L. Boone T. Shimamoto G. DeRose M. Elliot R. Colombero A. Tan H.-L. Trail G. Sullivan J. Davy E. Bucay N. Renshaw-Gegg L. Hughes T.M. Hill D. Pattison W. Campbell P. Sander S. Van G. Tarpley J. Derby P. Lee R. Boyle W.J. Cell. 1997; 89: 309-319Abstract Full Text Full Text PDF PubMed Scopus (4299) Google Scholar). Excluding NGF, each of these signaling pathways is likely to be involved in critical functions related to both the function and development of the immune system. For example, TNF acts primarily as an inflammatory cytokine coordinating host defenses in response to aggression by pathogens by activating a wide range of immunological and non-immunological mechanisms (13Vassalli P. Annu. Rev. Immunol. 1992; 10: 411-452Crossref PubMed Scopus (1798) Google Scholar). The LT system is involved in the development of the peripheral lymphoid organs and the organization of splenic architecture (14De Togni P. Goellner J. Ruddle N.H. Streeter P.R. Fick A. Mariathasan S. Smith S.C. Carlson R. Shornick L.P. Strauss-Schoenberger J. Russell J.H. Karr R. Chaplin D.D. Science. 1994; 264: 703-707Crossref PubMed Scopus (869) Google Scholar, 15Koni P.A. Sacca R. Lawton P. Browning J.L. Ruddle N.H. Flavell R.A. Immunity. 1997; 6: 491-500Abstract Full Text Full Text PDF PubMed Scopus (521) Google Scholar). CD40 is a key element in the regulation of the immunoglobulin response (16Foy T.M. Aruffo A. Bajorath J. Buhlmann J.E. Noelle R.J. Annu. Rev. Immunol. 1996; 14: 591-617Crossref PubMed Scopus (571) Google Scholar), and Fas signaling has been implicated in the mechanisms controlling peripheral tolerance and thymic selection (17Nagata S. Golstein P. Science. 1995; 267: 1449-1458Crossref PubMed Scopus (3965) Google Scholar, 18Castro J.E. Listman J.A. Jacobson B.A. Wang Y. Lopez P.A. Ju S. Finn P.W. Perkins D.L. Immunity. 1996; 5: 617-627Abstract Full Text PDF PubMed Scopus (136) Google Scholar). Other members such as OX-40, 4–1BB, CD27, and CD30 are also involved in the control of various aspects of the immune system (19Strueber E. Strober W. J. Exp. Med. 1996; 183: 979-989Crossref PubMed Scopus (243) Google Scholar, 20DeBenedette M.A. Chu N.R. Pollok K.E. Hurtako J. Wade W.F. Kwon B.S. Watts T.H. J. Exp. Med. 1995; 181: 985-992Crossref PubMed Scopus (165) Google Scholar, 21Agematsu K. Kobata T. Yang F.-C. Nakazawa T. Fukushima K. Kitahara M. Mori T. Sugita K. Morimoto C. Komiyama A. Eur. J. Immunol. 1995; 25: 2825-2829Crossref PubMed Scopus (80) Google Scholar, 22Amakawa R. Hakem A. Kundig T.M. Matsuyama T. Simard J.J.L. Timms E. Wakeham A. Mittruecker H.-W. Griesser H. Takimoto H. Schmits R. Shahinian A. Ohashi P.S. Penninger J.M. Mak T.W. Cell. 1996; 84: 551-562Abstract Full Text Full Text PDF PubMed Scopus (295) Google Scholar).Some of these receptors upon activation can directly trigger the apoptotic death of many transformed cells, e.g. TNF-R55, Fas, TRAIL-R, and TRAMP (23Nagata S. Cell. 1997; 88: 355-365Abstract Full Text Full Text PDF PubMed Scopus (4536) Google Scholar). Clearly, Fas and possibly TNF-R55 and CD30 activation can induce cell death in nontransformed lymphocytes, which may play an immunoregulatory function (22Amakawa R. Hakem A. Kundig T.M. Matsuyama T. Simard J.J.L. Timms E. Wakeham A. Mittruecker H.-W. Griesser H. Takimoto H. Schmits R. Shahinian A. Ohashi P.S. Penninger J.M. Mak T.W. Cell. 1996; 84: 551-562Abstract Full Text Full Text PDF PubMed Scopus (295) Google Scholar, 23Nagata S. Cell. 1997; 88: 355-365Abstract Full Text Full Text PDF PubMed Scopus (4536) Google Scholar, 24Zheng L. Fisher G. Miller R.E. Peschon J. Lynch D.H. Lenardo M.J. Nature. 1995; 377: 348-351Crossref PubMed Scopus (1049) Google Scholar, 25Sytwu H.-K. Liblau R.S. McDevitt H.O. Immunity. 1996; 5: 17-30Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar). In general, death is triggered following the aggregation of death domains that reside on the cytoplasmic side of the TNF receptors. The death domain orchestrates the assembly of various signal transduction components that result in the activation of the caspase cascade (23Nagata S. Cell. 1997; 88: 355-365Abstract Full Text Full Text PDF PubMed Scopus (4536) Google Scholar). Some receptors lack canonical death domains, e.g. LTβ receptor and CD30 (26Browning J.L. Miatkowski K. Sizing I. Griffiths D. Zafari M. Benjamin C.D. Meier W. Mackay F. J. Exp. Med. 1996; 183: 867-878Crossref PubMed Scopus (135) Google Scholar, 27Lee S.Y. Park C.G. Choi Y. J. Exp. Med. 1996; 183: 669-674Crossref PubMed Scopus (153) Google Scholar), yet can induce cell death, albeit more weakly. It is likely that these receptors function primarily to induce cell differentiation in vivo and the death is an aberrant consequence in some transformed cell lines, although this picture is unclear, as studies on the CD30 null mouse suggest a role in death during negative selection in the thymus (22Amakawa R. Hakem A. Kundig T.M. Matsuyama T. Simard J.J.L. Timms E. Wakeham A. Mittruecker H.-W. Griesser H. Takimoto H. Schmits R. Shahinian A. Ohashi P.S. Penninger J.M. Mak T.W. Cell. 1996; 84: 551-562Abstract Full Text Full Text PDF PubMed Scopus (295) Google Scholar). Conversely, signaling through other pathways such as CD40 is required to maintain cell survival.In this paper, we describe the mouse and human versions of a new member of this family, which we have called TWEAK. Like TNF, TWEAK is readily secreted from cells. Furthermore, we have prepared a recombinant soluble form of the molecule and used it to show that TWEAK signaling can induce cell death in an adenocarcinoma cell line.DISCUSSIONThis paper describes the molecular cloning, expression, and biological activity of a new member of the TNF family. Both the murine and human TWEAK proteins exhibit all the characteristics of this family, i.e. a type II membrane protein organization and conservation of the sequence motifs involved in the folding of the protein into the TNF anti-parallel β-sheet structure. All members of the TNF ligand family are believed to be compact trimers, and our biochemical analysis of TWEAK is consistent with this quaternary structure. A striking feature of TWEAK is the extensive sequence conservation of the receptor binding domain between mouse and man, and only the Fas ligand approaches this level of conservation. It is enticing to speculate that this sequence conservation reflects a critical functional role for TWEAK. Within the genome, both ligands and receptors in this family are often found in clusters of genes; however, the TWEAK gene does not lie within any known cluster, nor is it in a region with known disease linkage.TNF family members can best be described as master switches in the immune system controlling both cell survival and differentiation, although the recent description of bone density regulation by the TNF family member osteoprotegerin certainly suggests broader roles (12Simonet W.S. Lacey D.L. Dunstan C.R. Kelley M. Chang M.-S. Luethy R. Nguyen H.Q. Wooden S. Bennett L. Boone T. Shimamoto G. DeRose M. Elliot R. Colombero A. Tan H.-L. Trail G. Sullivan J. Davy E. Bucay N. Renshaw-Gegg L. Hughes T.M. Hill D. Pattison W. Campbell P. Sander S. Van G. Tarpley J. Derby P. Lee R. Boyle W.J. Cell. 1997; 89: 309-319Abstract Full Text Full Text PDF PubMed Scopus (4299) Google Scholar). There may be some clues to TWEAK's functional role from the limited characterization presented here. Only TNF and LTα and possibly Fas ligand are currently recognized as secreted cytokines, contrasting with the other predominantly membrane anchored members. While a membrane form of TNF has been well characterized and is likely to have a unique biological role, secreted TNF functions as a general alarm signaling to cells more distant from the site of the triggering event. Thus, TNF secretion can amplify a primary inflammatory event leading to the well described changes in the vascular lining and and consequent cell trafficking. In contrast, the membrane-bound members of the family send signals through the TNF type receptors only to cells in direct contact. For example T cells probably provide CD40-mediated “help” only to those B cells brought into contact via cognate interactions. The fact that TWEAK appears to be efficiently secreted suggests that its role will resemble that of TNF, i.e. to provide a long range signal. The presence of a possible AU-rich motif may indicate involvement in host defense.TWEAK RNA is abundantly expressed in many organs in a pattern reminiscent of TRAIL (5Wiley S.R. Schooley K. Smolak P.J. Din W.S. Huang C.-P. Nicholl J.K. Sutherland G.R. Smith T.D. Rauch C. Smith C.A. Goodwin R.G. Immunity. 1995; 3: 673-682Abstract Full Text PDF PubMed Scopus (2636) Google Scholar). Other TNF family members are typically more difficult to detect in tissue Northern blots, e.g. CD40 ligand or TNF, where expression is limited to very specific circumstances. While TWEAK RNA is abundant, it remains to be seen if protein expression is equally abundant. TWEAK and TRAIL expression patterns suggest more constitutive functions for these TNF family members, possibly indicating that they form a subclass within the family. The relative lack of TWEAK expression in hematopoietically derived tumor lines also points to a divergence from the standard TNF family ligand, which is typically expressed in lymphoid cells.TWEAK can induce chemokine secretion, which is likely to be a common feature of members of the TNF family. Chemokine regulation by TNF members may underlie several key aspects of their biology as is well described for TNF (38Degli-Esposti M. Davis-Smith T. Din W.S. Smolak P.J. Goodwin R.G. Smith C.A. J. Immunol. 1997; 158: 1756-1762PubMed Google Scholar, 39Abreu-Martin M.T. Vidrich A. Lynch D.H. Targan S.R. J. Immunol. 1995; 155: 4147-4154PubMed Google Scholar), but may also extend to the LT system and BRL-1-interacting chemokines (40Forster R. Mattis A.E. Kremmer E. Wolf E. Brem G. Lipp M. Cell. 1996; 87: 1037-1047Abstract Full Text Full Text PDF PubMed Scopus (951) Google Scholar). The ability to induce programmed cell death is also an important and well studied feature of several members of the TNF family. Fas-mediated apoptosis appears to play a role in the regulation of autoreactive lymphocytes in the periphery and possibly the thymus (18Castro J.E. Listman J.A. Jacobson B.A. Wang Y. Lopez P.A. Ju S. Finn P.W. Perkins D.L. Immunity. 1996; 5: 617-627Abstract Full Text PDF PubMed Scopus (136) Google Scholar, 23Nagata S. Cell. 1997; 88: 355-365Abstract Full Text Full Text PDF PubMed Scopus (4536) Google Scholar), and recent work has also implicated the TNF and CD30 systems in the survival of T cells and large cell anaplastic lymphoma lines (22Amakawa R. Hakem A. Kundig T.M. Matsuyama T. Simard J.J.L. Timms E. Wakeham A. Mittruecker H.-W. Griesser H. Takimoto H. Schmits R. Shahinian A. Ohashi P.S. Penninger J.M. Mak T.W. Cell. 1996; 84: 551-562Abstract Full Text Full Text PDF PubMed Scopus (295) Google Scholar, 24Zheng L. Fisher G. Miller R.E. Peschon J. Lynch D.H. Lenardo M.J. Nature. 1995; 377: 348-351Crossref PubMed Scopus (1049) Google Scholar, 25Sytwu H.-K. Liblau R.S. McDevitt H.O. Immunity. 1996; 5: 17-30Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar, 41Gruss H.J. Boiani N. Williams D.E. Armitage R.J. Smith C.A. Goodwin R.G. Blood. 1994; 83: 2045-2056Crossref PubMed Google Scholar). TWEAK induced cell death in a human adenocarcinoma cell line, HT29. We and others had previously shown that the death of this line in response to TNF, Fas, or LTβ receptor signaling has the features of apoptosis (26Browning J.L. Miatkowski K. Sizing I. Griffiths D. Zafari M. Benjamin C.D. Meier W. Mackay F. J. Exp. Med. 1996; 183: 867-878Crossref PubMed Scopus (135) Google Scholar, 39Abreu-Martin M.T. Vidrich A. Lynch D.H. Targan S.R. J. Immunol. 1995; 155: 4147-4154PubMed Google Scholar) and the death induced by TWEAK was similar to that triggered by Fas or TNF receptor activation. In contrast to the broad spectrum of Fas ligand- or TRAIL-sensitive cells, other TWEAK-sensitive cells were not readily found, and this pattern is similar to that described for LTβ receptor activation. Whether TWEAK has a function similar to Fas remains to be seen; however, the inability to kill the sensitive Jurkat and SKW 6.4 lines suggests that regulation of lymphocyte death or survival is not its role. LTβ receptor activation can induce growth arrest in some cell lines (38Degli-Esposti M. Davis-Smith T. Din W.S. Smolak P.J. Goodwin R.G. Smith C.A. J. Immunol. 1997; 158: 1756-1762PubMed Google Scholar), and our studies on the effects of LTβ receptor activation on the growth of tumors in vivo are also consistent with growth arrest as opposed to direct cell death. 4F. Mackay and J. Browning, unpublished observations. For these reasons, TWEAK is likely to induce cell differentiation in vivo and probably not cell death.It is possible to segregate the TNF receptor pairs into three groups based on their ability to induce cell death (TableIII). First, TNF-R55, Fas, TRAIL-RI (DR4), TRAIL-RII (DR5), and TRAMP (DR3/WSL-1/Apo-3) receptors can efficiently induce cell death in many lines, and these receptors have canonical death domains (8Pan G. O'Rourke K. Chinnaiyan A.M. Gentz R. Ebner R. Ni J. Dixit V.M. Science. 1997; 276: 111-113Crossref PubMed Scopus (1546) Google Scholar, 9Pan G. Ni J. Wei Y.-F. Yu G.-L. Gentz R. Dixit V.M. Science. 1997; 277: 815-818Crossref PubMed Scopus (1373) Google Scholar, 10Sheridan J.P. Marsters S.A. Pitti R.M. Gurney A. Skubatch M. Baldwin D. Ramakrishnan L. Gray C.L. Baker K. Wood W.I. Goddard A.D. Godowski P. Ashkenazi A. Science. 1997; 277: 818-821Crossref PubMed Scopus (1519) Google Scholar, 23Nagata S. Cell. 1997; 88: 355-365Abstract Full Text Full Text PDF PubMed Scopus (4536) Google Scholar). Next, there are those receptors that trigger a weaker death signal limited to a few cell types; the TWEAK, CD30, LTβ, and possibly the TNF-R75 (42Medvedev A.E. Sundan A. Espevik T. Eur. J. Immunol. 1994; 24: 2842-2849Crossref PubMed Scopus (52) Google Scholar, 43Grell M. Zimmermann G. Hulser D. Pfizenmaier K. Scheurich P. J. Immunol. 1994; 153: 1963-1972PubMed Google Scholar) and CD27 receptors (44Prasad K.V.S. Ao Z. Yoon Y. Wu M.X. Rizk M. Jacquot S. Schlossman S.F. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 6346-6351Crossref PubMed Scopus (250) Google Scholar) are examples of this class. Finally, there are those members that cannot efficiently deliver a death signal, and the possibility must be considered that these receptors have simply not been studied as well. Probably all groups can exhibit antiproliferative effects on some cell types consequent to inducing cell differentiation,e.g. CD40 (45Funakoshi S. Longo D.L. Beckwith M. Conley D.K. Tsarfaty G. Tsarfaty I. Armitage R.J. Fanslow W.C. Spriggs M.K. Murphy W.J. Blood. 1994; 83: 2787-2794Crossref PubMed Google Scholar).Table IIIGrouping of various TNF family signaling pathways by cytotoxicity patternsGroupReceptorPotent inducers of apoptosis in many cell typesTNF-R55, Fas, TRAIL-RI (DR4), TRAIL-RII (DR5), TRAMP (DR3)Weak inducers of apoptosis in a few cell typesLTβ-R, TWEAK-R,3-aTWEAK-R is presumed to exist. CD30, CD27, TNF-R75Do not induce cell deathCD40, OX-40, 4–1BB3-a TWEAK-R is presumed to exist. Open table in a new tab How the “weak death” group can trigger cell death in the absence of a canonical death domain is an interesting question and prompts speculation that an alternative entry point into the death-inducing caspase cascade exists. Specifically, in the case of HT29 cells, why does receptor signaling lead to death only in the presence of IFNγ? It is possible that these weak death receptors may activate the conventional death domain-mediated pathways via induction of the expression of Fas and Fas ligand or other receptor/ligands in the strong death group. In support of this concept, Fas expression is known to be up-regulated by IFNγ on HT29 cells, and the expression of Fas ligand by tumor lines as a possible immune surveillance escape mechanism has been described (46Yonehara S. Ishii A. Yonehara M. J. Exp. Med. 1989; 169: 1747-1756Crossref PubMed Scopus (1422) Google Scholar, 47Strand S. Hofmann W.J. Hug H. Mueller M. Otto G. Strand D. Mariani S.M. Stremmel W. Krammer P.H. Galle P.R. Nat. Med. 1996; 2: 1361-1366Crossref PubMed Scopus (876) Google Scholar, 48Hahne M. Rimoldi D. Schroeter M. Romero P. Schreier M. French L.E. Schneider P. Bornand T. Fontana A. Lienard D. Cerottini J.-C. Tschopp J. Science. 1996; 274: 1363-1366Crossref PubMed Scopus (1191) Google Scholar), although the anti-hFas-L blocking antibody, NOK-1, did not affect cell death in this system (data not shown). We have also observed that activation of the LTβ receptor can potentiate TNF signaling possibly reflecting favorable cross-talk between signaling pathways (26Browning J.L. Miatkowski K. Sizing I. Griffiths D. Zafari M. Benjamin C.D. Meier W. Mackay F. J. Exp. Med. 1996; 183: 867-878Crossref PubMed Scopus (135) Google Scholar, 49Mackay F. Bourdon P.R. Griffiths D.A. Lawton P. Zafari M. Sizing I.D. Miatkowski K. Ngam-ek A. Benjamin C.D. Hession C. Ambrose C.M. Meier W. Browning J.L. J. Immunol. 1997; 159: 3299-3310PubMed Google Scholar). Alternatively, weak death receptor signaling may differentiate the line into a state of unfulfilled growth factor dependence or cell cycle confusion with consequent initiation of the death pathway. A fourth possibility lies in the recent observations on the ability of NF-κB activation to inhibit the death signal delivered by death domain bearing receptors and IFNγ treatment may relieve the death repression by NF-κB (23Nagata S. Cell. 1997; 88: 355-365Abstract Full Text Full Text PDF PubMed Scopus (4536) Google Scholar). Since anti-Fas-induced HT29 cell death is IFNγ-dependent yet Fas signaling does not lead to NF-κB activation (23Nagata S. Cell. 1997; 88: 355-365Abstract Full Text Full Text PDF PubMed Scopus (4536) Google Scholar), regulation of downstream NF-κB-mediated events is less likely. Finally, and most likely, death may be initiated by other “non-FLICE”-initiated signaling pathways such as the ceramide or JNK/stress-activated protein kinase pathways (50Hannun Y.A. Nature. 1996; 274: 1855-1859Google Scholar, 51Yang X. Khosravi-Far R. Chang H.Y. Baltimore D. Cell. 1997; 89: 1067-1076Abstract Full Text Full Text PDF PubMed Scopus (823) Google Scholar). Whatever the mechanism, further exploration of the death trigger initiated by these weak death receptors may provide an additional approach to cancer therapy.The TNF family has grown dramatically in recent years to encompass at least 14 different ligand/receptor signaling pathways that regulate host defense and the immune system. The widespread expression patterns of TWEAK and TRAIL indicate that there may be considerably more functional variety to be uncovered in this family. This aspect was highlighted recently with the discovery of two new TNF receptors that affect the ability of Rous sarcoma and herpes simplex virus to productively infect cells along with the discovery of a bone density regulating receptor. When coupled with the historical observations that TNF itself has anti-viral activity and that pox viruses encode for decoy TNF receptors to avoid host defense, it appears that viral pathology and the functions of the TNF are interwoven (6Montgomery R.I. Warner M.S. Lum B.J. Spear P.G. Cell. 1996; 87: 427-436Abstract Full Text Full Text PDF PubMed Scopus (998) Google Scholar, 7Brojatsch J. Naughton J. Rolls M.M. Zingler K. Young J.A.T. Cell. 1996; 87: 845-855Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar, 13Vassalli P. Annu. Rev. Immunol. 1992; 10: 411-452Crossref PubMed Scopus (1798) Google Scholar, 52Smith G.L. Trends Microbiol. 1994; 3: 81-88Abstract Full Text PDF Scopus (100) Google Scholar). The generation of soluble TWEAK and the eventual identification of the TWEAK receptor should provide the tools to elucidate the biological function of this new pathway. Cytokines of the TNF 1The abbreviations used are: TNF, tumor necrosis factor; IL, interleukin; TNF-R, TNF receptor; NGF, nerve growth factor; RACE, rapid amplification of cDNA ends; LT, lymphotoxin; PCR, polymerase chain reaction; bp, base pair(s); kb, kilobase pair(s); EST, expressed sequence tag; PAGE, polyacrylamide gel electrophoresis; PBS, phosphate-buffered saline; FACS, fluorescence-activated cell sorting; IFN, interferon; EBNA, Epstein-Barr virus nuclear antigen; DAPI, 4′,6-diamidino-2-phenylindole. 1The abbreviations used are: TNF, tumor necrosis factor; IL, interleukin; TNF-R, TNF receptor; NGF, nerve growth factor; RACE, rapid amplification of cDNA ends; LT, lymphotoxin; PCR, polymerase chain reaction; bp, base pair(s); kb, kilobase pair(s); EST, expressed sequence tag; PAGE, polyacrylamide gel electrophoresis; PBS, phosphate-buffered saline; FACS, fluorescence-activated cell sorting; IFN, interferon; EBNA, Epstein-Barr virus nuclear antigen; DAPI, 4′,6-diamidino-2-phenylindole.family are mediators of host defense and immune regulation. Members of this family act either locally through direct cell-to-cell contact or as secreted proteins capable of diffusing to more distant targets. These proteins are synthesized as type II membrane proteins with the extracellular C-terminal region mediating binding to the receptors of the TNF receptor (TNF-R) family (1Smith C.A. Farrah T. Goodwin R.G. Cell. 1994; 76: 959-962Abstract Full Text PDF PubMed Scopus (1831) Google Scholar). The TNF family of ligands and receptors comprises at least 14 unique signaling pathways including TNF, lymphotoxins (LT), Fas, CD27, CD30, CD40, 4–1BB, OX-40, TRAMP (also DR3, WSL-1, Apo-3), CAR-1, TRAIL, GITR, HVEM, osteoprotegerin, and NGF (2Chinnaiyan A.M. O'Rourke K. Yu G.-L. Lyons R.H. Garg M. Duan D.R. Xing L. Gentz R. Ni J. Dixit V.M. Science. 1996; 274: 990-992Crossref PubMed Scopus (529) Google Scholar, 3Bodmer J.-L. Burns K. Schneider P. Hofmann K. Steiner V. Thome M. Bornand T. Hahne M. Schroeter M. Becker K. Wilson A. French L.E. 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• W2062462227 title "TWEAK, a New Secreted Ligand in the Tumor Necrosis Factor Family That Weakly Induces Apoptosis" @default.
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