Phagocytosis of necrotic cells by macrophages is phosphatidylserine dependent and does not induce inflammatory cytokine production

Apoptotic cells are cleared by phagocytosis during development, homeostasis, and pathology. However, it is still unclear how necrotic cells are removed. We compared the phagocytic uptake by macrophages of variants of L929sA murine fibrosarcoma cells induced to die by tumor necrosis factor-induced necrosis or by Fas-mediated apoptosis. We show that apoptotic and necrotic cells are recognized and phagocytosed by macrophages, whereas living cells are not. In both cases, phagocytosis occurred through a phosphatidylserine-dependent mechanism, suggesting that externalization of phosphatidylserine is a general trigger for clearance by macrophages. However, uptake of apoptotic cells was more efficient both quantitatively and kinetically than phagocytosis of necrotic cells. Electron microscopy showed clear morphological differences in the mechanisms used by macrophages to engulf necrotic and apoptotic cells. Apoptotic cells were taken up as condensed membrane-bound particles of various sizes rather than as whole cells, whereas necrotic cells were internalized only as small cellular particles after loss of membrane integrity. Uptake of neither apoptotic nor necrotic L929 cells by macrophages modulated the expression of proinflammatory cytokines by the phagocytes

Structure-function analysis of human interleukin-6 and its receptor

Doctorat en Sciencesinfo:eu-repo/semantics/nonPublishe

Restrictins: Stromal cell associated factors that control cell organization in hemopoietic tissues

Hemopoiesis is a sequence of events initiated by the self-renewal of pluripotent stem cells followed by a series of differentiation steps and completed in the formation of distinct tissue patterns. Differentiation and self-renewal are antagonistic processes. A mechanism that attenuates the differentiation flow is obligatory to prevent the exhaustion of the stem cell pool. We suggest that stromal cells from the bone marrow control stem cell renewal through a mechanism that does not require colony-stimulating factors. The organization of cells within the tissue and their specific localization is suggested to be directed by stromal cell activities other than differentiation inducers. These stromal cell activities restrict differentiation or accumulation of mature cells. They are therefore designated as 'Restrictins'.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Translation inhibition in apoptosis: caspase-dependent PKR activation and eIF2-α phosphorylation: Caspase-dependent PKR activation and eIF2-α phosphorylation

info:eu-repo/semantics/publishe

Translation inhibition in apoptosis - Caspase-dependent PKR activation and eIF2-alpha phosphorylation.

The protein kinase PKR is a major player in the cellular antiviral response, acting mainly by phosphorylation of the α-subunit of the eukaryotic translation initiation factor 2 (elF2-α) to block de novo protein synthesis. PKR activation requires binding of double-stranded RNA or PACT/RAX proteins to its regulatory domain. Since several reports have demonstrated that translation is inhibited in apoptosis, we investigated whether PKR and eIF2-α phosphorylation contribute to this process. We show that PKR is proteolysed and that eIF2-α is phosphorylated at the early stages of apoptosis induced by various stimuli. Both events coincide with the onset of caspase activity and are prevented by caspase inhibitors. Using site-directed mutagenesis we show that PKR is specifically proteolysed at Asp251 during cellular apoptosis. This site is cleaved in vitro by recombinant caspase-3, caspase-7, and caspase-8 and not by the proinflammatory caspase-1 and caspase-11. The released kinase domain efficiently phosphorylates eIF2-α at the cognate Ser51 residue, and its overexpression in mammalian cells impairs the translation of its own mRNA and of reporter mRNAs. Our results demonstrate a new and caspase-dependent activation mode for PKR, leading to eIF2-α phosphorylation and translation inhibition in apoptosis.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Protein synthesis during apostosis and necrosis: a comparative study

info:eu-repo/semantics/publishe

The Caspase-Generated Fragments of PKR Cooperate to Activate Full Length PKR and Inhibit Translation

info:eu-repo/semantics/publishe

Stroma-cell dependent hematopoiesis

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

The Caspase-Generated Fragments of PKR Cooperate to Activate Full Length PKR and Inhibit Translation

info:eu-repo/semantics/publishe

Apoptotic pathways and their regulation

Many studies have led to the identification of molecules involved in the signaling to cell death and especially to apoptosis. This cell death program is characterized by distinct morphological changes occurring both in the cytoplasm and the nucleus, including membrane blebbing, cytoplasm and chromatin condensation, DNA degradation and inhibition of protein translation. Apoptosis signaling can be initiated either at the cell surface through a receptor-induced signaling pathway, or from within the cell itself via the release of proapoptotic factors such as cytochrome c from triggered mitochondria. Stress occurring in other organelles, including the ER, nucleus and lysosomes, is also capable of initiating specific apoptotic pathways. The main executioners of the apoptotic pathways are proteases of the caspase family that function in a tightly regulated proteolytic cascade leading to the disintegration of the cell. Furthermore, apoptosis is regulated by a family of Bcl-2 like proteins, some of which promote cell death, while others are anti-apoptotic. Apoptosis in homeostasis and pathology is connected with phagocytosis. Several apoptotic pathways can be considered as packaging phenomena that allow silent, non-inflammatory removal of dying cells. The central role of apoptosis in homeostasis and cell renewal is also illustrated by the fact that anti-apoptotic mechanisms are crucial in tumorigenesis and therapeutic resistance. Recovery of an apoptotic response in these tumour cells or induction of an alternative cell death pathway, such as necrosis or autophagy, is very relevant for defining new anti-cancer treatments. © 2005 Springer Science+Business Media, Inc. All rights reserved.SCOPUS: ch.binfo:eu-repo/semantics/publishe