Apoptotic

The class II cytokine receptor family includes receptors for interferon a/P (lEN a/P) and y (lENy) and IL-10. lEN-y immunoreactivity has been found in neurons in the hypothalamus, cerebral cortex, mammilary nuclei, and dorsal tegmentum. Astrocytes and microglia in vitro can be stimulated to express class II histocompatibiHty complex (MHC-II) antigens by lEN-y, which may be involved in the presentation of antigen to T-ceUs by astrocytes. Thus lEN-y may be critical in CNS-immune function and dysfunction especially in regard to neuronal and gHal apoptotic processes. 

The main types of cellular injury induced by chemical compounds are necrotic and apoptotic (programmed) cell death. Necrosis implies chaotic ending... 

In apoptotic cell death, several factors such as growth factors, NO, the tumor suppressor gene p53, and the protein encoded by this gene contribute to the process that leads to cell death. One of the functions of p53 protein is the activation of apoptosis if a cell is transformed to a malignant cell. Apoptosis typically leads to the formation of smaller membrane-encapsulated particles within the cell. Apoptotic cell death begins in the nucleus and proceeds to other parts of the cell. The death process may be quite advanced before it can... 

TABLE 5.10 Some Important Biochemical Events in Apoptotic Control ... 

Tumors derived from hormone sensitive tissues may remain hormone dependent and are then amenable to therapeutic approaches with hormonal agents. These include hormones with opposing (apoptotic) action, hormone antagonists, and agents that inhibit hormone synthesis. 

Glucocorticoids have inhibitory (apoptotic) effects on lymphocyte proliferation and are used to treat leukemias and lymphomas. Estrogens (fosfestrol) are used to block the effect of androgens in prostate cancer. Progestogens (megestrol, medroxyprogesteroneacetate) have been useful for treating endometrial carcinoma, renal tumors, and breast cancer. 

There is also crosstalk between the two pathways above the mitochondria. The BH3-only protein BID is cleaved by caspase-8 and -10 which yields truncated BID (tBED), the active pro-apoptotic fragment of BID. Thereby, even in cells in which the direct apoptosis pathway which result from death receptor crosslinking is blocked, e.g. by high expression levels ofthex-linked IAP (XIAP), the activity of tBED on mitochondria can result in the activation of caspase-3 because the IAP-imposed block on full caspase-3 activation and caspase-9 activity at the apoptosome is released by Smac/ DIABLO. 

Apoptotic executioner caspases (caspase-3, -6, -7) constitute a subgroup of the caspase family. These proteases are the workhorses of the apoptotic process as they are responsible for cleaving many down-stream substrates important for cellular morphology, organelle homeostasis, cell cycle arrest, and regulation of transcription and translation. 

Apoptotic initiator caspases (caspase-2, -8, -9 and -10) constitute a subgroup of the caspase family. These caspases are the first to become proteolytically active in the apoptotic cascade. Their activation takes place in multiprotein complexes initiated by pro-apoptotic stimuli, such as TNFa, a-Fas, staurosporine. Once activated, they can process their substrates, which include the apoptotic executioner caspases. 

A substantial amount of indirect evidence supports the contention that the induction of apoptosis in tumor cells is critical to successful therapy. Cancer therapy might therefore be viewed as an attempt to induce apoptosis in a population of cells that have undergone selection for apoptotic defects. If correct, this hypothesis would suggest why cancer therapy is in many cases unsuccessful. However, recent studies indicate that this fundamental problem can be circumvented. Progress in the identification of molecules key to the cell death pathways has led to a growing understanding of how apoptosis occurs [3]. It has become clear that pathways to apoptosis are numerous and often interconnected. A solution to the clinical problem of therapeutic resistance, then, may lie in the fact that there appears to be multiple ways that a cell death program can be implemented. 

Apoptosis occurs as a result of a cascade ofproteolysis that culminates in the destruction of the cell. Apoptotic proteolysis is catalyzed by the caspase family of... 

Alterations to the P53 gene are the most common genetic defects known in cancer [5]. The protein product of P53 is involved in a number of pathways that directly and indirectly lead to apoptosis. Many genes that are involved in apoptosis can be induced by this protein, which is a transcriptional transactivator. The emerging hypothesis is that p53 is a central node of a complex apoptotic network that may function differ ently in diver se cell types and tissues. For example, Bax, the prototype proapoptotic member of the Bcl2 family, can be transcriptionally induced by p53 in certain, but not all, cell types. Like p53, Bax can modulate the extent to which cells are sensitive to apoptosis caused by therapeutic agents. 

Inhibition of inflammatory cytokines (Fig. 2) Humanized monoclonal anti-TNF antibodies (Infliximab (Remicade ), Adalimumab (Humira )) bind with high selectivity to human TNF-a and neutralize its activity. Thereby, infliximab decreases the effects of enhanced TNF levels during inflammatory disease such as production of proteases, chemokines, adhesion molecules, cyclooxygenase products (prostaglandins), and proinflammatory molecules such as interleukin-1 and -6. The antibodies may also recognize membrane-bound TNF-a on lymphocytes and other immune cells. These cells may subsequently become apoptotic or are eliminated via Fc-receptor-mediated phagocytosis. 

ET-1 also stimulates anti-apoptotic signal cascades in fibroblasts, vascular smooth muscles and endothelial cells (via phosphatidylinositol-3-kinase and Akt/pro-tein kinase B). In prostate and ovarian cancer, upregulation of endothelin synthesis and ETA receptors has been associated with a progression of the disease. The inhibiton of ETA receptors results in a reduced tumour growth. In malignant melanoma, ETB receptors are associated with tumour progression. Endothelins can also stimulate apoptosis in stretch-activated vessels via the ETB receptor, which contrasts the above-mentioned effects. The molecular basis for these differential anti- and pro-apoptotic reactions mediated by endothelins remains elusive. 

In the very early phases of the acute inflammatory response most of the cells invading the damaged area are polymorphonuclear neutrophils, also denoted as PMNs, which serve as initial line of defense and source of proinflammatory cytokines. These cells, which usually live for 4-5 days, circulate in the blood until they are attracted by chemokines into injured tissues. Whereas physical injury does not recruit many neutrophils, infections with bacteria or fungi elicit a striking neutrophil response. The characteristic pus of a bacterial abscess is composed mainly of apoptotic (apoptosis) and necrotic PMNs. Emigration of neutrophils from the blood starts with a process denoted as margination where neutrophils come to lie at the periphery of flowing blood cells and adhere to endothelial cells (Fig. 1). L-Selectin is expressed... 

Formation of apoptotic bodies which are engulfed and cleared by phagocytes... 

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