Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Signaling in Activated T Cells Abrogates TRAIL-Induced Apoptosis Upstream of the Mitochondrial Amplification Loop and Caspase-8

Abstract

Fas ligand and TNF-related apoptosis-inducing ligand (TRAIL) induce apoptosis in many different cell types. Jurkat T cells die rapidly by apoptosis after treatment with either ligand. We have previously shown that mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) can act as a negative regulator of apoptosis mediated by the Fas receptor. In this study we examined whether MAPK/ERK can also act as a negative regulator of apoptosis induced by TRAIL. Activated Jurkat T cells were efficiently protected from TRAIL-induced apoptosis. The protection was shown to be MAPK/ERK dependent and independent of protein synthesis. MAPK/ERK suppressed TRAIL-induced apoptosis upstream of the mitochondrial amplification loop because mitochondrial depolarization and release of cytochrome c were inhibited. Furthermore, caspase-8-mediated relocalization and activation of Bid, a proapoptotic member of the Bcl family, was also inhibited by the MAPK/ERK signaling. The protection occurred at the level of the apoptotic initiator caspase-8, as the cleavage of caspase-8 was inhibited but the assembly of the death-inducing signaling complex was unaffected. Both TRAIL and Fas ligand have been suggested to regulate the clonal size and persistence of different T cell populations. Our previous results indicate that MAPK/ERK protects recently activated T cells from Fas receptor-mediated apoptosis during the initial phase of an immune response before the activation-induced cell death takes place. The results of this study show clearly that MAPK/ERK also participates in the inhibition of TRAIL-induced apoptosis after T cell activation.

The mitogen-activated protein kinase pathway can inhibit TRAIL-induced apoptosis by prohibiting association of truncated Bid with mitochondria

“…[14][15][16][17][18] Accordingly, it is well known that MAPK activates genes implicated in cell survival. 19 To determine whether inhibition of TRAIL-induced apoptosis exerted by PKC activation is due to the novo synthesis of survival genes, MCF-7 cells were treated with TRAIL and PKC activator phorbol-12,13-dibutyrate (PDBu) in the presence or absence of the protein synthesis inhibitor cycloheximide (CHX) (Figure 1a).…”

“…[14][15][16]35 In contrast, in melanoma and breast cancer cell lines signaling through the MAPK/Erk pathway inhibits TRAIL-induced translocation of Bax from the cytosol to mitochondria thus preventing the release of apoptogenic factors from this organelle. 17,18 In the present report, we have demonstrated that in MCF-7 breast cancer cells TRAIL and TNF-a-induced cleavage of Bid was unaffected by PKC activation and identified the mitochondrial localization of tBid as a novel target of MAPK mediated apoptosis inhibition.…”

“…Activation of PKC has been suggested to inhibit TRAIL-induced apoptosis by preventing FADD recruitment to the DISC 14,15 or reducing the processing of procaspase-8. 16 On the other hand, it was reported that an activated MAPK pathway abrogated Smac/DIABLO release from mitochondria. 17 Our previous work indicated that the PKC-MAPK pathway impacted on the mitochondrial route of effector caspase activation.…”

ERK couples chronic survival of NK cells to constitutively activated Ras in lymphoproliferative disease of granular lymphocytes (LDGL)

“…It is known that MEK/ERK signaling suppresses Fasmediated apoptosis in activated T cells by inhibiting DISC-mediated activation of caspase 8. (Holmstrom et al, 2000;Tran et al, 2001;He et al, 2002;Soderstrom et al, 2002). Other antiapoptotic proteins such as Bcl-2 and BAD are regulated by activated MAPK and may contribute to survival in these NK cells.…”

Activation of p38 Mitogen-Activated Protein Kinase Is Required for Death Receptor–Independent Caspase-8 Activation and Cell Death in Response to Sphingosine

“…Concentrations of sphingosine and S1P in cell pellets were determined by HPLC following a previously described procedure with modification (33). Cell pellets were lysed with 0.2 N NaOH for the determination of protein content.…”