Tumor Necrosis Factor-alpha Activation of the c-Jun N-terminal Kinase Pathway in Human Neutrophils. INTEGRIN INVOLVEMENT IN A PATHWAY LEADING FROM CYTOPLASMIC TYROSINE KINASES TO APOPTOSIS (original) (raw)
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Genes & Development, 2004
The c-Jun NH 2 -terminal kinase (JNK) has been implicated in both cell death and survival responses to different stimuli. Here we reexamine the function of JNK in tumor necrosis factor (TNF)-stimulated cell death using fibroblasts isolated from wild-type, Mkk4 −/− Mkk7 −/− , and Jnk1 −/− Jnk2 −/− mice. We demonstrate that JNK can act to suppress TNF-stimulated apoptosis. However, we find that JNK can also potentiate TNF-stimulated necrosis by increasing the production of reactive oxygen species (ROS). Together, these data indicate that JNK can shift the balance of TNF-stimulated cell death from apoptosis to necrosis. Increased necrosis may represent a contributing factor in stress-induced inflammatory responses mediated by JNK.
Biochemical and Biophysical Research Communications, 1999
Early activation of c-Jun N-terminal kinase (JNK) is believed to block apoptosis in response to death signals such as tumor necrosis factor (TNF). Brief exposure of murine L929 fibroblasts to anisomycin for 1 hr to activate JNK resulted in resistance to TNF killing. TNF rapidly induced cytoplasmic shrinkage in control cells, but not in the anisomycin-pretreated L929 cells. However, the induced TNF resistance was suppressed in the L929 cells which were engineered to stably inhibit ⌱〉␣ protein expression by antisense mRNA (ϳ80% reduction in protein expression). No constitutive NF-B nuclear translocation and increased TNF resistance were found in these ⌱〉␣ antisense cells. Notably, these cells had a significantly reduced basal level of JNK activation (50 -70%), compared to vector control cells. Furthermore, brief exposure of L929 cells to wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3-kinase), resulted in resistance to TNF killing, probably due to preconsumption of caspases by wortmannin. Nonetheless, wortmannin-induced TNF resistance was suppressed in the ⌱〉␣ antisense cells. Thus, these observations indicate that ⌱〉␣ is essential for maintaining the basal level of JNK activation and regulating the JNK-induced TNF resistance.
Journal of Biological Chemistry, 1998
Fas ligand and tumor necrosis factor ␣ (TNF) bind to members of the TNF receptor superfamily. Stimulation by Fas ligand results in apoptosis, whereas TNF induces multiple effects including proliferation, differentiation, and apoptosis. Activation of the c-Jun N-terminal kinase (JNK) and p38 kinase pathways is common to Fas and TNF signaling; however, their role in apoptosis is controversial. Fas receptor cross-linking induces apoptosis in the absence of actinomycin D and activates JNK in a caspase-dependent manner. In contrast, TNF requires actinomycin D for apoptosis and activates JNK and p38 kinase with biphasic kinetics. The first phase is transient, precedes apoptosis, and is caspase-independent, whereas the second phase is coincident with apoptosis and is caspase-dependent. Inhibition of early TNF-induced JNK and p38 kinases using MKK4/MKK6 mutants or the p38 inhibitor SB203580 increases TNF-induced apoptosis, whereas expression of wild type MKK4/MKK6 enhances survival. In contrast, the Mek inhibitor PD098059 has no effect on survival. These results demonstrate that early activation of p38 kinase (but not Mek) are necessary to protect cells from TNF-mediated cytotoxicity. Thus, early stress kinase activation initiated by TNF plays a key role in regulating apoptosis. Fas ligand (FasL) 1 and tumor necrosis factor ␣ (TNF) bind to members of the TNF receptor superfamily (1). Fas/CD95/ APO-1 receptor oligomerization induced by FasL or by agonist antibodies results in apoptosis in a variety of cells, including T, B, and NK cells, macrophages, and fibroblasts (2). TNF binds to two ubiquitously expressed receptors, TNF receptor I (TNFRI/ p55) and TNF receptor II (TNFRII/p75), that do not share any homology within their cytoplasmic domains (3). Unlike FasL, TNF elicits a wide range of cellular effects, including apoptosis, proliferation, differentiation, inflammation, and chemotaxis (4). FasL and TNF activate apoptotic signaling pathways through a similar mechanism. Fas and TNF interact either directly or indirectly with the adapter protein FADD/MORT1, which recruits caspase 8 to the receptor complex (reviewed in Ref. 3). The resulting cascade of caspase activation causes cleavage of cytosolic, cytoskeletal, and nuclear proteins and
Cell, 1996
to be transduced by TNFR1, many can also be mediated by TNFR2 (Tartaglia and Goeddel, 1992; Smith et al., and Michael Karin* 1994; Vandenabeele et al., 1995). TNFR2, however, is a *Department of Pharmacology poor inducer of apoptosis. Program in Biomedical Sciences Exposure to TNF results in activation of two transcrip-School of Medicine tion factors, AP-1 (Brenner et al., 1989) and NF-B (Os-University of California, San Diego born et al., 1989). These transcription factors mediate La Jolla, California 92093-0636 induction of other cytokine and immunoregulatory † Tularik Incorporated genes, as well as metalloproteinases. Several second Two Corporate Drive messengers have been proposed to mediate the biologi-South San Francisco, California 94080 cal effects of TNFR ligation, including various phospholipid breakdown products, arachidonic acid metabolites, free radicals, and increased intracellular Ca 2ϩ (reviewed Summary by Beyaert and Fiers, 1994). However, as discussed by Beyaert and Fiers, (1994), it is not clear whether these Through its type 1 receptor (TNFR1), the cytokine TNF are true second messengers or secondary effects of elicits an unusually wide range of biological re-TNFR activation. Several protein kinases were found to sponses, including inflammation, tumor necrosis, cell be activated rapidly in response to TNF, including yetproliferation, differentiation, and apoptosis. We investo-be-identified ceramide-activated kinase (Weigmann tigated how TNFR1 activates different effector funcet al., 1994), IB kinase (DiDonato et al., 1996), and a tions; the protein kinase JNK, transcription factor NF-TNFR1-associated serine/threonine kinase (VanArsdale B, and apoptosis. We found that the three responses and Ware, 1994), as well as the molecularly identified are mediated through separate pathways. Recruit-Raf-1 (Belka et al., 1995), Jun N-terminal kinases (JNKs; ment of the signal transducer FADD to the TNFR1 Minden et al., 1994), and p38/Mpk2 (Raingeaud et al., complex mediates apoptosis but not NF-B or JNK 1995). Activation of the IB kinase results in NF-B actiactivation. Two other signal transducers, RIP and vation (Verma et al., 1995; DiDonato et al., 1996), while TRAF2, mediate both JNK and NF-B activation. These Raf-1, JNK, and p38/Mpk2 activation contribute to intwo responses, however, diverge downstream to duction of AP-1 activity (Karin, 1995). The pathways by TRAF2. Most importantly, JNK activation is not inwhich TNFR ligation causes activation of these protein volved in induction of apoptosis, while activation of kinases are not clear. Recently, much emphasis has NF-B protects against TNF-induced apoptosis. been placed on the potential role of ceramide as a mediator of TNF signaling. TNF-induced phospholipid hydro
Biochemical …, 2002
The activation of the extracellular signal-regulated kinases (ERKs) by tumour necrosis factor-α (TNF) receptors (TNFRs) is an integral part of the cytokine's pleiotropic cellular responses. Here we report differences in the caspase sensitivity and TNFR subtype activation of members of the ERK family. Inhibition in HeLa cells of caspase function by pharmacological inhibitors or the expression of CrmA (cytokine response modifier A), a viral modifier protein, blocks TNF-induced apoptosis or caspasedependent protein kinase Cδ and poly(ADP-ribose) polymerase protein degradation. TNFR1-or TNFR2-stimulated c-Jun N-terminal kinase (JNK) activity was attenuated in cells in which caspase activity was inhibited either by pharmacological blockers or CrmA expression. Both TNFR1-and TNFR2stimulated JNK activity was caspase-sensitive ; however, only TNFR1 was capable of stimulating p42\44 mitogen-activated
Journal of Biological Chemistry, 1998
Fas ligand and tumor necrosis factor ␣ (TNF) bind to members of the TNF receptor superfamily. Stimulation by Fas ligand results in apoptosis, whereas TNF induces multiple effects including proliferation, differentiation, and apoptosis. Activation of the c-Jun N-terminal kinase (JNK) and p38 kinase pathways is common to Fas and TNF signaling; however, their role in apoptosis is controversial. Fas receptor cross-linking induces apoptosis in the absence of actinomycin D and activates JNK in a caspase-dependent manner. In contrast, TNF requires actinomycin D for apoptosis and activates JNK and p38 kinase with biphasic kinetics. The first phase is transient, precedes apoptosis, and is caspase-independent, whereas the second phase is coincident with apoptosis and is caspase-dependent. Inhibition of early TNF-induced JNK and p38 kinases using MKK4/MKK6 mutants or the p38 inhibitor SB203580 increases TNF-induced apoptosis, whereas expression of wild type MKK4/MKK6 enhances survival. In contrast, the Mek inhibitor PD098059 has no effect on survival. These results demonstrate that early activation of p38 kinase (but not Mek) are necessary to protect cells from TNF-mediated cytotoxicity. Thus, early stress kinase activation initiated by TNF plays a key role in regulating apoptosis. Fas ligand (FasL) 1 and tumor necrosis factor ␣ (TNF) bind to members of the TNF receptor superfamily (1). Fas/CD95/ APO-1 receptor oligomerization induced by FasL or by agonist antibodies results in apoptosis in a variety of cells, including T, B, and NK cells, macrophages, and fibroblasts (2). TNF binds to two ubiquitously expressed receptors, TNF receptor I (TNFRI/ p55) and TNF receptor II (TNFRII/p75), that do not share any homology within their cytoplasmic domains (3). Unlike FasL, TNF elicits a wide range of cellular effects, including apoptosis, proliferation, differentiation, inflammation, and chemotaxis (4). FasL and TNF activate apoptotic signaling pathways through a similar mechanism. Fas and TNF interact either directly or indirectly with the adapter protein FADD/MORT1, which recruits caspase 8 to the receptor complex (reviewed in Ref. 3). The resulting cascade of caspase activation causes cleavage of cytosolic, cytoskeletal, and nuclear proteins and
Role of p38-Mitogen-Activated Protein Kinase in Spontaneous Apoptosis of Human Neutrophils
Journal of Immunology, 1999
Neutrophils constitutively undergo apoptosis at both normal and inflamed sites: an important process that limits the toxic potential of the neutrophil. However, the signal pathway for neutrophil apoptosis is currently unknown. In this study, we evaluated the role of p38-mitogen-activated protein kinase (MAPK) in the spontaneous apoptosis of neutrophils in vitro. We found that p38-MAPK was constitutively tyrosine phosphorylated and activated during spontaneous apoptosis of neutrophils. Inhibition of p38-MAPK by SB203580 and an antisense oligonucleotide delayed apoptosis by approximately 24 h. The antioxidants catalase and N-acetylcysteine delayed neutrophil apoptosis, but failed to inhibit phosphorylation and activation of p38-MAPK. Granulocyte-macrophage CSF and anti-Fas Ab, which altered the rate of apoptosis, did not affect phosphorylation and activation of p38-MAPK. These results suggest that the constitutive phosphorylation and activation of p38-MAPK are involved in the program of spontaneous apoptosis in neutrophils.
Molecular and Cellular Biology, 2002
The proinflammatory cytokine tumor necrosis factor alpha (TNF-α) regulates immune responses, inflammation, and programmed cell death (apoptosis). TNF-α exerts its biological activities by activating multiple signaling pathways, including IκB kinase (IKK), c-Jun N-terminal protein kinase (JNK), and caspases. IKK activation inhibits apoptosis through the transcription factor NF-κB, whose target genes include those that encode inhibitors of both caspases and JNK. Despite activation of the antiapoptotic IKK/NF-κB pathway, TNF-α is able to induce apoptosis in cells sensitive to it, such as human breast carcinoma MCF-7 and mouse fibroblast LM cells. The molecular mechanism underlying TNF-α-induced apoptosis is incompletely understood. Here we report that in TNF-α-sensitive cells activation of the IKK/NF-κB pathway fails to block TNF-α-induced apoptosis, although its inactivation still promotes TNF-α-induced apoptosis. Interestingly, TNF-α-induced apoptosis is suppressed by inhibition of t...