Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.61 (caspase-8)
 6,833 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The immune system attempts to prevent or limit tumor growth, yet efforts to induce responses to tumors yield minimal results, rendering tumors virtually invisible to the immune system [1]. Several mechanisms may account for this subversion, including the triggering of tolerance to tumor antigens [2, 3], TGF-alpha or IL-10 production, downregulation of MHC molecules, or upregulation of FasL expression [4, 5]. Melanoma cells may in some instances use FasL expression to protect themselves against tumor-infiltrating lymphocytes (TIL) [4, 5]. Here, we show another, chemokine-dependent mechanism by which melanoma tumor cells shield themselves from immune reactions. Melanoma-inducible CCL5 (RANTES) production by infiltrating CD8 cells activates an apoptotic pathway in TIL involving cytochrome c release into the cytosol and activation of caspase-9 and -3. This process, triggered by CCL5 binding to CCR5, is not mediated by TNFalpha, Fas, or caspase-8. The effect is not unique to CCL5, as other CCR5 ligands such as CCL3 (MIP-1alpha) and CCL4 (MIP-1beta) also trigger TIL cell death, nor is it limited to melanoma cells, as it also operates in activated primary T lymphocytes. The model assigns a role to the CXC chemokine CXCL12 (SDF-1alpha) in this process, as this melanoma cell-produced chemokine upregulates CCL5 production by TIL, initiating TIL cell death.
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PMID:A potential immune escape mechanism by melanoma cells through the activation of chemokine-induced T cell death. 1136 32

Human caspase-4 does not have a corresponding mouse ortholog. Caspase-4 falls within the class of "inflammatory caspases," being homologous with human caspases 1 and 5 and mouse caspases 1, 11, and 12. To address the function of caspase-4, we generated caspase-4-deficient human THP1 monocytic cell lines which exhibited substantially reduced LPS-induced secretion of several chemokines and cytokines, including IL-8 (CXCL8), CCL4 (macrophage-inflammatory protein-1beta), CCL20 (macrophage-inflammatory protein-3alpha), and IL-1beta. The LPS-induced expression of the mRNAs encoding these cytokines was correspondingly reduced in the caspase-4-deficient clones. Because a specific NF-kappaB inhibitor blocked LPS-induced IL-8 and CCL4 mRNA expression as well as IL-8 and CCL4 secretion in THP1 cells, we investigated the role of caspase-4 in NF-kappaB signaling. LPS-induced NF-kappaB nuclear translocation and activation were inhibited in all caspase-4-deficient clones. LPS stimulation led to the interaction of endogenous caspase-4 and TNFR-associated factor 6 (TRAF6) via a TRAF6-binding motif (PPESGE), which we identified in caspase-4. Mutation of this site in caspase-4 resulted in the loss of the TRAF6-caspase-4 interaction. Similar TRAF6-binding motifs are known to be functionally important for TRAF6 interactions with other molecules including caspase-8, and for mediating NF-kappaB activation in various immune and nonimmune cell types. Our data suggest that the TRAF6-caspase-4 interaction, triggered by LPS, leads to NF-kappaB-dependent transcriptional up-regulation and secretion of important cytokines and chemokines in innate immune signaling in human monocytic cells.
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PMID:Caspase-4 interacts with TNF receptor-associated factor 6 and mediates lipopolysaccharide-induced NF-kappaB-dependent production of IL-8 and CC chemokine ligand 4 (macrophage-inflammatory protein-1 ). 1805 95

Vgamma9 Vdelta2 T lymphocytes are involved in the immune response against hematological malignancies and certain pathogens through the recognition of nonpeptidic Ags expressed by tumors and infected cells. Being equipped with proinflammatory chemokine receptors, they participate to the early phases of inflammation acting as both effector and connector cells between innate and adaptive immunity. We show in this study that after initial TCR triggering short- and long-term cultured gammadelta lymphocytes differ in their susceptibility to activation-induced apoptosis and proinflammatory phenotype. Activation-induced apoptosis was triggered by anti-CD95 mAbs or by the gammadeltaTCR stimuli isopentenyl pyrophosphate and pamidronate, the latter in the presence of monocytes. In particular, short-term cultured cells are resistant to apoptosis and characterized by expression of anti-apoptotic cellular FLIP molecules and partial spontaneous caspase-8 activation. Linked to this behavior, short-term gammadelta cells display constitutive activation of the transcription factor NF-kappaB, which is functionally related to their apoptosis-resistant phenotype. Finally, they spontaneously secreted elevated amounts of the NF-kappaB-regulated chemokines CCL3, CCL4, and CCL5, which likely contributed to down-modulation of the inflammatory CCR5 receptor. Conversely, long-term cultured apoptosis-sensitive gammadelta cells displayed uncleaved caspase-8 and no constitutive NF-kappaB activation; moreover, they secreted CC chemokines only upon TCR triggering coupled to the re-expression of CCR5. The expression of members of the TNF receptor family, including CD30 and TNFRII, also varied according to the time in culture. Altogether our data support a link between resistance to apoptosis and a proinflammatory phenotype in gammadelta T lymphocytes, unraveling the crucial role of NF-kappaB in regulating the switch from resistance to apoptosis susceptibility.
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PMID:NF-kappa B modulates sensitivity to apoptosis, proinflammatory and migratory potential in short- versus long-term cultured human gamma delta lymphocytes. 1894 Nov 74