Page 957 - Williams Hematology ( PDFDrive )

932 Part VII: Neutrophils, Eosinophils, Basophils, and Mast Cells Chapter 60: Structure and Composition of Neutrophils, Eosinophils, and Basophils 933

proteins, contact allergy, or skin allograft rejection is present. They have PROTEIN SYNTHESIS BY MATURE
been shown to be rich sources of IL-4 and IL-13. 83,84,88 NEUTROPHILS
Mast cells are normal residents of connective tissue throughout
the body. Mast cell granules contain various substances, including Mature neutrophils have been classically viewed as terminally differ-
several preformed biologically active substances such as histamine, entiated cells without the ability to synthesize proteins. This view has
which causes increased vascular permeability; eosinophil che- changed as a result of numerous investigations in vitro and in vivo show-
motactic factor of anaphylaxis; and heparin, which has antith- ing that neutrophils can synthesize numerous proteins (e.g., cytokines,
rombin activity. 89–92 This accounts for the metachromatic staining chemokines, growth factors, interferons) potentially important to the
quality of the granules. The generation of anaphylatoxin (C3a, C5a) inflammatory process and the regulation of immune reactions. Table 60–3
or the interaction of allergen with immunoglobulin (Ig) E recep- lists some of the proteins expressed by mature neutrophils. The data-
tors of plasma membrane can stimulate extracellular release of these base for these observations has been extensively reviewed, 107,108 and
granule contents and of several newly formed substances, such as some potentially important concepts are discussed here. As is evident
slow-reacting substance of anaphylaxis, a leukotriene that causes from this list, the diversity is impressive, but the extent of production
contraction of human bronchioles and increased vascular perme- of each protein by individual neutrophils is limited when compared to
ability, and platelet-activating factor (PAF), which causes platelet mononuclear cells. However, because neutrophils make up the majority
aggregation and the subsequent release of serotonin. This phenom- of infiltrating cells early in an acute inflammatory process, often emi-
90
enon is called IgE-mediated mast cell degranulation. Mast cells grating in massive numbers, their aggregate synthetic ability may be
also have been implicated in various diseases that are accompanied significant to the course of the inflammatory or healing response. In
by neovascularization (Chap. 63). vitro, an array of stimuli have been used to induce protein expression,
including lipopolysaccharide (LPS), cytokines, chemotactic factors,
adhesive ligands, opsonized particles, and modulatory cytokines such
METABOLISM OF NEUTROPHILS as IL-10 and IL-4.
The signaling pathways leading to new protein synthesis are sub-
CARBOHYDRATE METABOLISM jects of extensive studies and are briefly described here. Granulocyte
colony-stimulating factor (G-CSF), granulocyte-macrophage colony-
Glycolysis stimulating factor (GM-CSF), and IL-10 have the ability to activate signal
Glycolytic (Embden-Meyerhof) Pathway The main energy- transducer and activator of transcription (STAT) proteins in neutrophils.
producing pathway in the neutrophil is glycolysis, resulting in the con- Both STAT-1 and STAT-3 and the upstream kinase Janus-associated
version of glucose to lactate. 93–95 When intact or homogenized leukocytes kinase 2 (JAK2) are rapidly tyrosine phosphorylated. 109,110 Neutrophils
are incubated with glucose uniformly labeled with C, approximately express nuclear factor κB-1 (NFκB1)/p50, p65/RelA, and c-Rel. Tumor
14
80 percent of the radioactivity is recovered in lactic acid. Glycolysis is necrosis factor-α (TNF-α), IL-1β, and IL-15 lead to the rapid loss of
inhibited by cortisol. 96,97 In some cases, the conditions under which the IκBα and the concomitant nuclear accumulation of NFκB/Rel proteins.
neutrophils are disrupted have a significant effect on the activities mea- This pathway is not activated by G-CSF, GM-CSF, IL-8, or IL-10. PU.1 is
sured. Hexokinase is the rate-limiting enzyme of glycolysis in normal expressed in mature neutrophils and constitutively binds DNA, and the
98
neutrophils. The rate of glycolysis is not altered during phagocytosis, AP-1 transcription factor is evident. Several of the inflammatory medi-
95
94
but ATP levels, normally 1.9 nmol/10 cells, fall to 0.8 nmol/10 cells. ators produced by mature neutrophils are AP-1 driven (e.g., TNF, IL-1,
6
6
Both the glycogen stores of neutrophils and the glucose of the plasma IL-8, intercellular adhesion molecule [ICAM]). Production of the CXC
68
can serve as the source of glucose. Galactose, mannose, and fructose can chemokine IL-8 by neutrophils has been extensively studied, and a wide
also be metabolized by leukocytes. Table 60–2 shows the glycolytic and range of stimuli can induce its expression. Cytokines such as TNF-α,
99
111
other principal enzymes of the neutrophil. IL-15, IL-1β, and GM-CSF; chemotactic factors such as C5a, PAF, and
leukotriene B (LTB ); particles such as monosodium urate crystals;
4
4
Hexose Monophosphate Shunt Pathway microbial products such as LPS and zymosan; interaction with antibody
Neutrophils also metabolize glucose by way of the hexose mono- and complement opsonized bacteria and yeasts; and interactions with
phosphate shunt, 100–102 thus accounting for some of the oxygen extracellular matrix molecules such as laminin and fibronectin, all have
consumption of the cells. In resting cells, the amount of glucose been shown to induce synthesis of IL-8 by neutrophils. In most studies,
metabolized via this route amounts to only 2 to 3 percent of the release of significant amounts of protein from the neutrophils and syn-
total glucose consumed by the cell. 101–103 The operation of the hexose thesis of mRNA have been demonstrated. Immunocytochemistry and in
monophosphate shunt, however, is of special importance to the situ hybridization studies have provided evidence of IL-8 production in
neutrophil, because this pathway provides the NADPH needed for neutrophils infiltrating inflammatory sites.
generation of microbicidal oxidants. Some of the stimuli that induce expression of IL-8 also stimulate
production by mature neutrophils of other proinflammatory agents,
such as growth-regulated protein (GRO)-α, TNF-α, IL-1β, oncostatin
Glycogen Metabolism M, and C-C chemokines. In addition, neutrophils may produce anti-
Neutrophils contain a large quantity of glycogen arising mostly from inflammatory agents such as IL-1RA and transforming growth factor
glucose. Little net synthesis from substrates occurs at the triose phos- (TGF)-β, and of interest is the observation that cytokines such as IL-10
phate level. Glycogen turnover increases when these cells are deprived may have some selectivity with regard to induction of antiinflammatory
of glucose, especially if they are engaged in phagocytosis, but resyn- factors in neutrophils. Thus, considerable evidence exists for protein
thesis occurs when adequate glucose is added. 95,104,105 During phago- synthesis capability in neutrophils, but because this field of study is rel-
cytosis by glucose-starved cells, glycogen phosphorylase activity atively new, much work remains to define the importance of the various
rises, but phosphorylase kinase and glycogen synthase levels remain proteins to inflammation, immune reactions and healing, the selectiv-
unchanged. Glycogen first appears in myelocytes and increases with ity of the conditions, and disease states linked to the synthetic activi-
105
cell maturation. 106 ties of neutrophils. In keeping with its critical role in the inflammatory

Kaushansky_chapter 60_p0923-0938.indd 932 9/18/15 10:35 PM