Tumor Necrosis Factor (TNF) and Phorbol Ester Induce TNF-related Apoptosis-inducing Ligand (TRAIL) under Critical Involvement of NF-κB Essential Modulator (NEMO)/IKKγ

We show that tumor necrosis factor (TNF) and phorbol 12-myristate 13-acetate (PMA) induce TNF-related apoptosis-inducing ligand (TRAIL) in T cells. In cells deficient for NF-κB essential modulator (NEMO)/IKKγ, an essential component of the NF-κB-inducing I-κB kinase (IKK) complex, induction of TRAIL expression was completely abrogated but was recovered in cells restored for IKKγ expression. In cells deficient for receptor-interacting protein expression TNF, but not PMA-induced TRAIL expression was blocked. Inhibition of protein synthesis with cycloheximide blocked PMA, but not TNF-induced up-regulation of TRAIL. As both TNF and PMA rapidly induce NF-κB activation this suggests that NEMO/IKKγ-dependent activation of the NF-κB pathway is necessary but not sufficient for up-regulation of TRAIL in T cells. The capability of the NF-κB pathway to induce the potent death ligand TRAIL may explain the reported proapoptotic features of this typically antiapoptotic pathway. We show that tumor necrosis factor (TNF) and phorbol 12-myristate 13-acetate (PMA) induce TNF-related apoptosis-inducing ligand (TRAIL) in T cells. In cells deficient for NF-κB essential modulator (NEMO)/IKKγ, an essential component of the NF-κB-inducing I-κB kinase (IKK) complex, induction of TRAIL expression was completely abrogated but was recovered in cells restored for IKKγ expression. In cells deficient for receptor-interacting protein expression TNF, but not PMA-induced TRAIL expression was blocked. Inhibition of protein synthesis with cycloheximide blocked PMA, but not TNF-induced up-regulation of TRAIL. As both TNF and PMA rapidly induce NF-κB activation this suggests that NEMO/IKKγ-dependent activation of the NF-κB pathway is necessary but not sufficient for up-regulation of TRAIL in T cells. The capability of the NF-κB pathway to induce the potent death ligand TRAIL may explain the reported proapoptotic features of this typically antiapoptotic pathway. tumor necrosis factor TNF-related apoptosis inducing ligand Fas ligand interferon NF-κB essential modulator FLICE-inhibitory protein monoclonal antibody receptor-interacting protein I-κB kinase phorbol 12-myristate 13-acetate/ionomycin phytohemagglutinin cycloheximide Tumor necrosis factor (TNF)1-related apoptosis-inducing ligand (TRAIL)/Apo2L belongs to the TNF ligand family and induces apoptosis in a broad range of tumor cells with apparently no cytotoxic activity on most nontransformed cells. TRAIL mRNA was found in a variety of tissues, in particular in activated T cells, and is often induced by interferons (1Wang Q. Ji Y. Wang X. Evers B.M. Biochem. Biophys. Res. Commun. 2000; 276: 466-471Crossref PubMed Scopus (88) Google Scholar). TRAIL interacts with five different members of the TNF receptor superfamily: TRAIL-R1/DR4, TRAIL-R2/DR5/TRICK2/Killer, TRAIL-R3/TRID/DcR1/LIT, TRAIL-R4/TRUNDD/DcR2 and osteoprotegerin (2Locksley R.M. Killeen N. Lenardo M.J. Cell. 2001; 104: 487-501Abstract Full Text Full Text PDF PubMed Scopus (2962) Google Scholar). TRAIL-R1 and TRAIL-R2 contain a death domain and mediate the apoptotic response toward TRAIL. TRAIL-R3, lacking a cytoplasmic domain, is anchored to the cell surface by modification with glycophospholipids and is regarded as a decoy receptor for TRAIL. TRAIL-R4 has an incomplete cytoplasmic death domain and is therefore incapable of signaling apoptosis but is still able to activate the antiapoptotic NF-κB pathway. Thus, TRAIL-R4 is maybe involved in regulation of the apoptotic TRAIL response at the cellular level. The soluble receptor osteoprotegerin, which otherwise has a critical role in regulation of osteoclastogenesis, may act as a systemic negative regulator of TRAIL-induced apoptosis (1Wang Q. Ji Y. Wang X. Evers B.M. Biochem. Biophys. Res. Commun. 2000; 276: 466-471Crossref PubMed Scopus (88) Google Scholar).TRAIL is involved in the induction of cell death by activated CD4+ T cells (3Thomas W.D. Hersey P. J. Immunol. 1998; 161: 2195-2200PubMed Google Scholar, 4Kayagaki N. Yamaguchi N. Nakayama M. Kawasaki A. Akiba H. Okumura K. Yagita H. J. Immunol. 1999; 162: 2639-2647PubMed Google Scholar), dendritic cells (5Fanger N.A. Maliszewski C.R. Schooley K. Griffith T.S. J. Exp. Med. 1999; 190: 1155-1164Crossref PubMed Scopus (355) Google Scholar), and NK cells (6Zamai L. Ahmad M. Bennett I.M. Azzoni L. Alnemri E.S. Perussia B. J. Exp. Med. 1998; 188: 2375-2380Crossref PubMed Scopus (414) Google Scholar). TRAIL may also play a role in activation-induced T cell death during HIV infection (7Katsikis P.D. Garcia-Ojeda M.E. Torres-Roca J.F. Tijoe I.M. Smith C.A. Herzenberg L.A. Herzenberg L.A. J. Exp. Med. 1997; 186: 1365-1372Crossref PubMed Scopus (179) Google Scholar, 8Jeremias I. Herr I. Boehler T. Debatin K.M. Eur. J. Immunol. 1998; 28: 143-152Crossref PubMed Scopus (264) Google Scholar, 9Miura Y. Misawa N. Maeda N. Inagaki Y. Tanaka Y. Ito M. Kayagaki N. Yamamoto N. Yagita H. Mizusawa H. Koyanagi Y. J. Exp. Med. 2001; 193: 651-660Crossref PubMed Scopus (116) Google Scholar). Inhibition of endogenous TRAIL enhances proliferation of autoreactive lymphocytes or synovial cells, thereby contributing to the exacerbation of arthritic inflammation and joint tissue destruction (10Song K. Chen Y. Goke R. Wilmen A. Seidel C. Goke A. Hilliard B. J. Exp. Med. 2000; 191: 1095-1104Crossref PubMed Scopus (322) Google Scholar). These data argue for an in vivofunction of TRAIL in the maintenance of immune homeostasis by counteracting autoimmune responses. However, in contrast to FasL, TRAIL inhibits autoimmune inflammation by inhibition of cell cycle progression instead of induction of T cell apoptosis (10Song K. Chen Y. Goke R. Wilmen A. Seidel C. Goke A. Hilliard B. J. Exp. Med. 2000; 191: 1095-1104Crossref PubMed Scopus (322) Google Scholar). In accordance with its remarkable tumoricidal activity in vitro, several studies point to a role of TRAIL in anti-tumoral immunity. In this regard, it has been recently shown that TRAIL is the sole principle mediating antitumorigenic activity of interferon-activated human monocytes (11Griffith T.S. Wiley S.R. Kubin M.Z. Sedger L.M. Maliszewski C.R. Fanger N.A. J. Exp. Med. 1999; 189: 1343-1354Crossref PubMed Scopus (412) Google Scholar). Moreover, up-regulation of TRAIL plays a central role in IFNγ-mediated antimetastatic effects of interleukin-12 and α-galactosylceramide (12Takeda K. Hayakawa Y. Smyth M.J. Kayagaki N. Yamaguchi N. Kakuta S. Iwakura Y. Yagita H. Okumura K. Nat. Med. 2001; 7: 94-100Crossref PubMed Scopus (587) Google Scholar, 13Smyth M.J. Cretney E. Takeda K. Wiltrout R.H. Sedger L.M. Kayagaki N. Yagita H. Okumura K. J. Exp. Med. 2001; 193: 661-670Crossref PubMed Scopus (420) Google Scholar). Further, aside the capability of dendritic cells to apoptotic cells to to cytotoxic T cells B. N. 1998; PubMed Scopus Google Scholar, L.M. B. P. N. J. Exp. Med. 1998; 188: PubMed Scopus Google Scholar), dendritic cells mediate cellular apoptosis TRAIL with or (5Fanger N.A. Maliszewski C.R. Schooley K. Griffith T.S. J. Exp. Med. 1999; 190: 1155-1164Crossref PubMed Scopus (355) Google Scholar). a that induce the of monocytes dendritic cells C. M. S. M. T. J. Exp. Med. 2000; 191: PubMed Scopus Google Scholar). Moreover, TRAIL expression on human T cells that TRAIL to the cytotoxic activity of in for the of and cell N. Yamaguchi N. Nakayama M. H. Okumura K. Yagita H. J. Exp. Med. 1999; 189: PubMed Scopus Google Scholar). In accordance with an of the death TRAIL T. N. M. P. H. 2001; PubMed Scopus Google and R. R. S.R. S. Nat. 1997; PubMed Scopus Google been as of In this show that TRAIL is induced by TNF and with phorbol critical of an essential component of the NF-κB signaling may for of the apoptotic effects for NF-κB in the PubMed Scopus Google Scholar, C. N. J. B. Cell. Full Text PDF PubMed Scopus Google Scholar, K.M. 2000; PubMed Scopus Google Scholar, S. A. Nat. Med. Scholar, R. Q. B. C. A. Nat. 2001; PubMed Scopus Google a for by TNF or during with TNF or a of by TNF and induced up-regulation of TRAIL mRNA but with TNF-induced TRAIL expression and a TRAIL induction by was for several and of TRAIL induction was also found in was no for an up-regulation of TRAIL in the cell and that TRAIL up-regulation by TNF and is cell and TNF a to induce TRAIL expression in the range as the TRAIL In of different that in at different In accordance with the in cells to TRAIL protein in cells or cell However, protein by in of cells no TRAIL was in the cells with during the of a of found in the TRAIL protein was also in of cells with and protein The of the and to the of the soluble TRAIL the domain of the ligand Eur. J. Immunol. 1998; 28: PubMed Scopus Google Scholar). The of the and in accordance with that of that of TRAIL. to the of that induces the of TRAIL as M.J. A. S. I. P. L. A. J. J. Immunol. 1999; Google inducing of TRAIL. In T cells also up-regulation of and TRAIL-R2 and in the induced TRAIL-R1 and TRAIL-R2 of cells with PMA or that PMA is sufficient for the induction of TRAIL not and both potent of the NF-κB pathway in cells We therefore this pathway to TRAIL induction in T cells. this a cell deficient in expression of L. M. M.E. I. 2000; PubMed Scopus Google Scholar), an essential of the NF-κB-inducing I-κB kinase (IKK) M. Y. Immunol. 2000; PubMed Scopus Google Scholar). These cells to with NF-κB activation to a variety of NF-κB TNF and PMA, but show activation of and I. M.E. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). As shown in both TNF and up-regulation of TRAIL was completely in this cell However, in a the cell in which NF-κB been restored by with an IKKγ expression I. M.E. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar), of the TRAIL toward and TNF was restored Further, up-regulation of but not was in the cells of the NF-κB pathway in TRAIL-R2 expression is in with studies a critical role of the of NF-κB in expression of TRAIL-R1 and TRAIL-R2 R. Q. B. C. A. Nat. 2001; PubMed Scopus Google Scholar). of of the NF-κB pathway for induction in cells has been I. M.E. J. 2000; Full Text Full Text PDF PubMed Scopus Google and suggests that the death TRAIL and during T cell activation by at signaling In the of TNF-induced TRAIL expression the of the NF-κB pathway in a deficient in expression B. J. PubMed Scopus Google Scholar). The kinase was as a Fas death but is also of the signaling and plays an essential role in NF-κB activation H. M. P. 1999; PubMed Scopus Google Scholar). of expression TNF-induced up-regulation of TRAIL but no on up-regulation of TRAIL and TRAIL-R2 not and induce TRAIL critical of the NF-κB pathway. cells with TNF or the and for NF-κB activation by of and NF-κB cells with of a NF-κB by and the cells with TNF or As a with the which with NF-κB an cells and for the cell and as as an of the for with or TNF for and of with a to the and as data argue for an essential of and therefore most the NF-κB pathway in and TRAIL expression. However, the data the TRAIL induction or We therefore the capability of TNF and to induce in the of of the cycloheximide TRAIL expression was completely in the of up-regulation was not by this Thus, TRAIL TNF induces TRAIL expression As interferons of for an of endogenous interferons in up-regulation of TRAIL. However, found no for an of interferons in up-regulation of TRAIL. receptor or to not Moreover, is most also not involved in up-regulation of TRAIL of As both and TNF rapidly activate NF-κB essential of and the for protein synthesis the of NF-κB up-regulation of TRAIL the of a pathway that with the NF-κB pathway to induce TRAIL and is induced by TNF but by However, the that TRAIL induction by an pathway the NF-κB which activated by and to the found no for a NF-κB of an of the TRAIL not induced the cytotoxic ligand TRAIL and of its death the of the cells was not However, the cells to apoptosis in the of to the induction of recently shown that induces up-regulation of a potent of death receptor signaling S. P. Cell. 2001; PubMed Scopus Google Scholar, Moreover, of with cells a with TRAIL or with an with the broad range TRAIL-induced apoptosis was completely blocked by and cell death was by both is in accordance with that in the of TRAIL induces cell death the death domain in cell death a pathway N. R. M. A. S. P. B. J. Nat. 2000; Scopus Google Scholar, H. Y. Y. A. Y. S. J. 2000; PubMed Scopus Google Scholar). blocked TRAIL-induced induced cell death in a of the cells and I. M.E. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). of of a of cells in which of and maybe but not TNF-induced up-regulation of TRAIL protein cells for the with in the or of and by cells for with TNF in the or of and by of and cells a TRAIL and cells in at a of and in with the of or TRAIL with or In cells with TRAIL or of cells by the Tumor necrosis factor (TNF)1-related apoptosis-inducing ligand (TRAIL)/Apo2L belongs to the TNF ligand family and induces apoptosis in a broad range of tumor cells with apparently no cytotoxic activity on most nontransformed cells. TRAIL mRNA was found in a variety of tissues, in particular in activated T cells, and is often induced by interferons (1Wang Q. Ji Y. Wang X. Evers B.M. Biochem. Biophys. Res. Commun. 2000; 276: 466-471Crossref PubMed Scopus (88) Google Scholar). TRAIL interacts with five different members of the TNF receptor superfamily: TRAIL-R1/DR4, TRAIL-R2/DR5/TRICK2/Killer, TRAIL-R3/TRID/DcR1/LIT, TRAIL-R4/TRUNDD/DcR2 and osteoprotegerin (2Locksley R.M. Killeen N. Lenardo M.J. Cell. 2001; 104: 487-501Abstract Full Text Full Text PDF PubMed Scopus (2962) Google Scholar). TRAIL-R1 and TRAIL-R2 contain a death domain and mediate the apoptotic response toward TRAIL. TRAIL-R3, lacking a cytoplasmic domain, is anchored to the cell surface by modification with glycophospholipids and is regarded as a decoy receptor for TRAIL. TRAIL-R4 has an incomplete cytoplasmic death domain and is therefore incapable of signaling apoptosis but is still able to activate the antiapoptotic NF-κB pathway. Thus, TRAIL-R4 is maybe involved in regulation of the apoptotic TRAIL response at the cellular level. The soluble receptor osteoprotegerin, which otherwise has a critical role in regulation of osteoclastogenesis, may act as a systemic negative regulator of TRAIL-induced apoptosis (1Wang Q. Ji Y. Wang X. Evers B.M. Biochem. Biophys. Res. Commun. 2000; 276: 466-471Crossref PubMed Scopus (88) Google Scholar). TRAIL is involved in the induction of cell death by activated CD4+ T cells (3Thomas W.D. Hersey P. J. Immunol. 1998; 161: 2195-2200PubMed Google Scholar, 4Kayagaki N. Yamaguchi N. Nakayama M. Kawasaki A. Akiba H. Okumura K. Yagita H. J. Immunol. 1999; 162: 2639-2647PubMed Google Scholar), dendritic cells (5Fanger N.A. Maliszewski C.R. Schooley K. Griffith T.S. J. Exp. Med. 1999; 190: 1155-1164Crossref PubMed Scopus (355) Google Scholar), and NK cells (6Zamai L. Ahmad M. Bennett I.M. Azzoni L. Alnemri E.S. Perussia B. J. Exp. Med. 1998; 188: 2375-2380Crossref PubMed Scopus (414) Google Scholar). TRAIL may also play a role in activation-induced T cell death during HIV infection (7Katsikis P.D. Garcia-Ojeda M.E. Torres-Roca J.F. Tijoe I.M. Smith C.A. Herzenberg L.A. Herzenberg L.A. J. Exp. Med. 1997; 186: 1365-1372Crossref PubMed Scopus (179) Google Scholar, 8Jeremias I. Herr I. Boehler T. Debatin K.M. Eur. J. Immunol. 1998; 28: 143-152Crossref PubMed Scopus (264) Google Scholar, 9Miura Y. Misawa N. Maeda N. Inagaki Y. Tanaka Y. Ito M. Kayagaki N. Yamamoto N. Yagita H. Mizusawa H. Koyanagi Y. J. Exp. Med. 2001; 193: 651-660Crossref PubMed Scopus (116) Google Scholar). Inhibition of endogenous TRAIL enhances proliferation of autoreactive lymphocytes or synovial cells, thereby contributing to the exacerbation of arthritic inflammation and joint tissue destruction (10Song K. Chen Y. Goke R. Wilmen A. Seidel C. Goke A. Hilliard B. J. Exp. Med. 2000; 191: 1095-1104Crossref PubMed Scopus (322) Google Scholar). These data argue for an in vivofunction of TRAIL in the maintenance of immune homeostasis by counteracting autoimmune responses. However, in contrast to FasL, TRAIL inhibits autoimmune inflammation by inhibition of cell cycle progression instead of induction of T cell apoptosis (10Song K. Chen Y. Goke R. Wilmen A. Seidel C. Goke A. Hilliard B. J. Exp. Med. 2000; 191: 1095-1104Crossref PubMed Scopus (322) Google Scholar). In accordance with its remarkable tumoricidal activity in vitro, several studies point to a role of TRAIL in anti-tumoral immunity. In this regard, it has been recently shown that TRAIL is the sole principle mediating antitumorigenic activity of interferon-activated human monocytes (11Griffith T.S. Wiley S.R. Kubin M.Z. Sedger L.M. Maliszewski C.R. Fanger N.A. J. Exp. Med. 1999; 189: 1343-1354Crossref PubMed Scopus (412) Google Scholar). Moreover, up-regulation of TRAIL plays a central role in IFNγ-mediated antimetastatic effects of interleukin-12 and α-galactosylceramide (12Takeda K. Hayakawa Y. Smyth M.J. Kayagaki N. Yamaguchi N. Kakuta S. Iwakura Y. Yagita H. Okumura K. Nat. Med. 2001; 7: 94-100Crossref PubMed Scopus (587) Google Scholar, 13Smyth M.J. Cretney E. Takeda K. Wiltrout R.H. Sedger L.M. Kayagaki N. Yagita H. Okumura K. J. Exp. Med. 2001; 193: 661-670Crossref PubMed Scopus (420) Google Scholar). Further, aside the capability of dendritic cells to apoptotic cells to to cytotoxic T cells B. N. 1998; PubMed Scopus Google Scholar, L.M. B. P. N. J. Exp. Med. 1998; 188: PubMed Scopus Google Scholar), dendritic cells mediate cellular apoptosis TRAIL with or (5Fanger N.A. Maliszewski C.R. Schooley K. Griffith T.S. J. Exp. Med. 1999; 190: 1155-1164Crossref PubMed Scopus (355) Google Scholar). a that induce the of monocytes dendritic cells C. M. S. M. T. J. Exp. Med. 2000; 191: PubMed Scopus Google Scholar). Moreover, TRAIL expression on human T cells that TRAIL to the cytotoxic activity of in for the of and cell N. Yamaguchi N. Nakayama M. H. Okumura K. Yagita H. J. Exp. Med. 1999; 189: PubMed Scopus Google Scholar). In accordance with an of the death TRAIL T. N. M. P. H. 2001; PubMed Scopus Google and R. R. S.R. S. Nat. 1997; PubMed Scopus Google been as of In this show that TRAIL is induced by TNF and with phorbol critical of an essential component of the NF-κB signaling may for of the apoptotic effects for NF-κB in the PubMed Scopus Google Scholar, C. N. J. B. Cell. Full Text PDF PubMed Scopus Google Scholar, K.M. 2000; PubMed Scopus Google Scholar, S. A. Nat. Med. Scholar, R. Q. B. C. A. Nat. 2001; PubMed Scopus Google Scholar). a for by TNF or during with TNF or a of by TNF and induced up-regulation of TRAIL mRNA but with TNF-induced TRAIL expression and a TRAIL induction by was for several and of TRAIL induction was also found in was no for an up-regulation of TRAIL in the cell and that TRAIL up-regulation by TNF and is cell and TNF a to induce TRAIL expression in the range as the TRAIL In of different that in at different In accordance with the in cells to TRAIL protein in cells or cell However, protein by in of cells no TRAIL was in the cells with during the of a of found in the TRAIL protein was also in of cells with and protein The of the and to the of the soluble TRAIL the domain of the ligand Eur. J. Immunol. 1998; 28: PubMed Scopus Google Scholar). The of the and in accordance with that of that of TRAIL. to the of that induces the of TRAIL as M.J. A. S. I. P. L. A. J. J. Immunol. 1999; Google inducing of TRAIL. In T cells also up-regulation of and TRAIL-R2 and in the induced TRAIL-R1 and TRAIL-R2 of cells with PMA or that PMA is sufficient for the induction of TRAIL not and both potent of the NF-κB pathway in cells We therefore this pathway to TRAIL induction in T cells. this a cell deficient in expression of L. M. M.E. I. 2000; PubMed Scopus Google Scholar), an essential of the NF-κB-inducing I-κB kinase (IKK) M. Y. Immunol. 2000; PubMed Scopus Google Scholar). These cells to with NF-κB activation to a variety of NF-κB TNF and PMA, but show activation of and I. M.E. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). As shown in both TNF and up-regulation of TRAIL was completely in this cell However, in a the cell in which NF-κB been restored by with an IKKγ expression I. M.E. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar), of the TRAIL toward and TNF was restored Further, up-regulation of but not was in the cells of the NF-κB pathway in TRAIL-R2 expression is in with studies a critical role of the of NF-κB in expression of TRAIL-R1 and TRAIL-R2 R. Q. B. C. A. Nat. 2001; PubMed Scopus Google Scholar). of of the NF-κB pathway for induction in cells has been I. M.E. J. 2000; Full Text Full Text PDF PubMed Scopus Google and suggests that the death TRAIL and during T cell activation by at signaling In the of TNF-induced TRAIL expression the of the NF-κB pathway in a deficient in expression B. J. PubMed Scopus Google Scholar). The kinase was as a Fas death but is also of the signaling and plays an essential role in NF-κB activation H. M. P. 1999; PubMed Scopus Google Scholar). of expression TNF-induced up-regulation of TRAIL but no on up-regulation of TRAIL and TRAIL-R2 not data argue for an essential of and therefore most the NF-κB pathway in and TRAIL expression. However, the data the TRAIL induction or We therefore the capability of TNF and to induce in the of of the cycloheximide TRAIL expression was completely in the of up-regulation was not by this Thus, TRAIL TNF induces TRAIL expression As interferons of for an of endogenous interferons in up-regulation of TRAIL. However, found no for an of interferons in up-regulation of TRAIL. receptor or to not Moreover, is most also not involved in up-regulation of TRAIL of As both and TNF rapidly activate NF-κB essential of and the for protein synthesis the of NF-κB up-regulation of TRAIL the of a pathway that with the NF-κB pathway to induce TRAIL and is induced by TNF but by However, the that TRAIL induction by an pathway the NF-κB which activated by and to the found no for a NF-κB of an of the TRAIL not induced the cytotoxic ligand TRAIL and of its death the of the cells was not However, the cells to apoptosis in the of to the induction of recently shown that induces up-regulation of a potent of death receptor signaling S. P. Cell. 2001; PubMed Scopus Google Scholar, Moreover, of with cells a with TRAIL or with an with the broad range TRAIL-induced apoptosis was completely blocked by and cell death was by both is in accordance with that in the of TRAIL induces cell death the death domain in cell death a pathway N. R. M. A. S. P. B. J. Nat. 2000; Scopus Google Scholar, H. Y. Y. A. Y. S. J. 2000; PubMed Scopus Google Scholar). blocked TRAIL-induced induced cell death in a of the cells and I. M.E. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). of of a of cells in which of and maybe but not TNF-induced up-regulation of TRAIL protein cells for the with in the or of and by cells for with TNF in the or of and by of and cells a TRAIL and cells in at a of and in with the of or TRAIL with or In cells with TRAIL or of cells by the In a for by TNF or during with TNF or a of by TNF and induced up-regulation of TRAIL mRNA but with TNF-induced TRAIL expression and a TRAIL induction by was for several and of TRAIL induction was also found in was no for an up-regulation of TRAIL in the cell and that TRAIL up-regulation by TNF and is cell and TNF a to induce TRAIL expression in the range as the TRAIL In of different that in at different In accordance with the in cells to TRAIL protein in cells or cell However, protein by in of cells no TRAIL was in the cells with during the of a of found in the TRAIL protein was also in of cells with and protein The of the and to the of the soluble TRAIL the domain of the ligand Eur. J. Immunol. 1998; 28: PubMed Scopus Google Scholar). The of the and in accordance with that of that of TRAIL. to the of that induces the of TRAIL as M.J. A. S. I. P. L. A. J. J. Immunol. 1999; Google inducing of TRAIL. In T cells also up-regulation of and TRAIL-R2 and in the induced TRAIL-R1 and TRAIL-R2 of cells with PMA or that PMA is sufficient for the induction of TRAIL not TNF and both potent of the NF-κB pathway in cells We therefore this pathway to TRAIL induction in T cells. this a cell deficient in expression of L. M. M.E. I. 2000; PubMed Scopus Google Scholar), an essential of the NF-κB-inducing I-κB kinase (IKK) M. Y. Immunol. 2000; PubMed Scopus Google Scholar). These cells to with NF-κB activation to a variety of NF-κB TNF and PMA, but show activation of and I. M.E. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). As shown in both TNF and up-regulation of TRAIL was completely in this cell However, in a the cell in which NF-κB been restored by with an IKKγ expression I. M.E. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar), of the TRAIL toward and TNF was restored Further, up-regulation of but not was in the cells of the NF-κB pathway in TRAIL-R2 expression is in with studies a critical role of the of NF-κB in expression of TRAIL-R1 and TRAIL-R2 R. Q. B. C. A. Nat. 2001; PubMed Scopus Google Scholar). of of the NF-κB pathway for induction in cells has been I. M.E. J. 2000; Full Text Full Text PDF PubMed Scopus Google and suggests that the death TRAIL and during T cell activation by at signaling In the of TNF-induced TRAIL expression the of the NF-κB pathway in a deficient in expression B. J. PubMed Scopus Google Scholar). The kinase was as a Fas death but is also of the signaling and plays an essential role in NF-κB activation H. M. P. 1999; PubMed Scopus Google Scholar). of expression TNF-induced up-regulation of TRAIL but no on up-regulation of TRAIL and TRAIL-R2 not Thus, data argue for an essential of and therefore most the NF-κB pathway in and TRAIL expression. However, the data the TRAIL induction or We therefore the capability of TNF and to induce in the of of the cycloheximide TRAIL expression was completely in the of up-regulation was not by this Thus, TRAIL TNF induces TRAIL expression As interferons of for an of endogenous interferons in up-regulation of TRAIL. However, found no for an of interferons in up-regulation of TRAIL. receptor or to not Moreover, is most also not involved in up-regulation of TRAIL of As both and TNF rapidly activate NF-κB essential of and the for protein synthesis the of NF-κB up-regulation of TRAIL the of a pathway that with the NF-κB pathway to induce TRAIL and is induced by TNF but by However, the that TRAIL induction by an pathway the NF-κB which activated by and to the found no for a NF-κB of an of the TRAIL not induced the cytotoxic ligand TRAIL and of its death the of the cells was not However, the cells to apoptosis in the of to the induction of recently shown that induces up-regulation of a potent of death receptor signaling S. P. Cell. 2001; PubMed Scopus Google Scholar, Moreover, of with cells a with TRAIL or with an with the broad range TRAIL-induced apoptosis was completely blocked by and cell death was by both is in accordance with that in the of TRAIL induces cell death the death domain in cell death a pathway N. R. M. A. S. P. B. J. Nat. 2000; Scopus Google Scholar, H. Y. Y. A. Y. S. J. 2000; PubMed Scopus Google Scholar). blocked TRAIL-induced induced cell death in a of the cells and I. M.E. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). of of a of cells in which of and maybe We for the and for the cell as as for the TRAIL and a of of and