The Functional Nucleus by David P. Bazett-Jones & Graham Dellaire

Author:David P. Bazett-Jones & Graham Dellaire
Language: eng
Format: epub
Publisher: Springer International Publishing, Cham

Keywords

Genome organizationChromosome territoriesNuclear architectureSpatial positioningGene positioningDiseaseCancerTranslocationsChromatin structureInflammationCytokinesSenescenceROSDNA damage responseNFκBNuclear laminaPML nuclear bodiesCancer

1 Introduction

1.1 Inflammation

Inflammation represents a complex response to infection and to damaged cells, tissue injury, allergens and other harmful stimuli. The acute inflammatory response involves the recruitment of plasma proteins and leukocytes, including neutrophils, macrophages and/or mast cells, from the blood vessels to the site of the infection or injury. A successful outcome is considered to be the recovery from infection, repair of tissue damage and restoration of homeostasis, which is accompanied by the resolution phase when leukocytes undergo programmed cell death and apoptotic cells are cleared by macrophage-mediated phagocytosis (Savill et al. 1989).

The inflammatory response is orchestrated by various plasma- and cell-derived mediators. The plasma-mediators include among others the fragments of the complement components (Markiewski and Lambris 2007). Cell-derived mediators are secreted from the participating leukocytes—mainly the mast cells and macrophages—and they include vasoactive amines histamine and serotonin, lipid mediators such as eicosanoids, chemokines such as interleukin 8 (IL8) and pro-inflammatory cytokines (i.e., IL1, IL6, IL11, and TNFα). The transcription factor NFκB (nuclear factor of kappa light polypeptide gene enhancer in B-cells) is activated by crucial pro-inflammatory cytokines TNFα (tumor necrosis factor alpha) and IL1 while their expression, together with the expression of other pro-inflammatory genes, is in turn upregulated by this transcription factor (discussed in detail below). Activated neutrophils at the afflicted site are equipped to fight the invading pathogens by a wide range of different proteases that are released from their granules and by the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS).

In the case of a persistent infection, extended exposure to a toxic agent or as a consequence of an autoimmune disease the inflammation persists and is termed as the chronic inflammation. Major cells involved in the chronic inflammation response are macrophages and, in case of an infection, also lymphocytes. While some cytokines are involved in both acute and chronic inflammation signaling (such as IL1, IL6 and TNFα), some other cytokines come into play when the inflammatory response persists and these include, for example, TGFβ (transforming growth factor beta) or interferons (IFNs). In contrast to the acute response, the continuous low-grade chronic inflammation has a role in tissue destruction and is linked to a whole range of diseases including aging, Alzheimer’s disease, atherosclerosis, cancer, cardiovascular diseases, dementia, neurological diseases, rheumatoid arthritis or type I diabetes mellitus. How acute and chronic inflammation contributes to structural changes in the nucleus, that in turn alter cellular homeostasis and contribute to disease processes, is only beginning to be explored and is the focus of this chapter.

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