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286 Part IV: Molecular and Cellular Hematology Chapter 19: The Inflammatory Response 287

cyclic guanosine monophosphate (cGMP) and, through the activation TABLE 19–4. Interleukin-1 and Tumor Necrosis Factor in
of a series of kinases, induces smooth-muscle relaxation and vasodi-
lation. Three different forms of NOS have been characterized: endo- Inflammation
35
35
thelial (eNOS), neuronal (nNOS), and inducible (iNOS). Nitric oxide Acute-phase response
can be produced either constitutively (eNOS, nNOS) or induced (iNOS) Fever
in a wide variety of cell types (e.g., endothelial cells, neurons, macro-
phages, respectively). Nitric oxide produced by eNOS plays a particu- Shock
larly important role in the localized regulation of vascular tone, whereas Neutrophilia
NO derived from nNOS is important in neuronal signal transduction. Somnolence
NO also plays important roles in the inhibition of smooth-muscle
proliferation and in inflammation. The roles of NO in inflammation Anorexia
include inhibition of cell-mediated inflammation, reduction in platelet Endothelial activation
aggregation and adhesion, and as a regulator of leukocyte recruitment. Induction of IL-1, IL-6, IL-8
Specifically, NO produced by cytokine-iNOS reduces leukocyte recruit-
ment into sites of inflammation. NO can react with reactive oxygen Procoagulant phenotype
intermediates to form both reactive oxygen and nitrogen species (e.g., Inhibition of fibrinolysis
−
−
NO + O → NO + HO•); it can inhibit DNA synthesis; it can directly Leukocyte adherence
2
2
kill microbes and tumor cells; and it can inactivate cytosolic glutathione
and other sulfhydryl enzymes. NO and its generating enzymes, eNOS, Fibroblast activation
nNOS, and iNOS, represent a regulatory system that has varied effects Proliferation
on the inflammatory response depending upon location and setting. Collagen synthesis
Collagenase and protease induction
LYSOSOMAL GRANULE CONSTITUENTS
The activation of neutrophils, monocytes and macrophages results in the
release, either through exocytosis or as the result of cell death, of a wide
variety of proinflammatory mediators that have important roles in the Elevated local (and sometimes systemic) concentrations of TNF-α,
inflammatory response. Neutrophils contain three major types of gran- IL-1β, and IL-6 are consistently observed during the development of
ules and also secretory vesicles (Chap. 60). Large, primary (azurophilic) an inflammatory response. Based on their roles in the systemic acute-
granules contain myeloperoxidase, lysozyme, a variety of cationic pro- phase response and in the orchestration of important localized mech-
teins, defensins, phospholipase, acid hydrolases and neutral proteases anistic steps in inflammation (e.g., induction of endothelial leukocyte
(e.g., proteinase 3, collagenases, elastase). Smaller, secondary (specific) adhesion molecules, phagocyte activation, procoagulant mediator
granules contain lactoferrin, lysozyme, type IV collagenase, subunits of induction), these mediators are prototypic “proinflammatory” cytok-
NADPH oxidase and the β -integrin, CD11b/CD18. Tertiary granules ines. Their expression is regulated by nuclear factor κB (NFκB). NFκB is
2
contain gelatinase, subunits of NADPH oxidase and CD11b/CD18. a transcription factor that exists as a heterodimer complexed with IκB
3,6
Acid proteases function most efficiently within phagolysosomes where (inhibitor κB) in the cytosol of many different cells types. When cells
the pH is low, whereas neutral proteases can function efficiently within are activated by various microbial products, viruses, reactive oxygen
extracellular inflammatory exudates. Lysosomal granule constituents intermediates, cytokines, and chemotherapeutic agents, IκB is phospho-
contribute to the inflammatory response and tissue injury through a rylated before it dissociates from NFκB heterodimers. Unbound NFκB
wide array of mechanisms (e.g., degradation of extracellular matrix, translocates into the cell nucleus where it participates in the upregula-
proteolytic generation of chemotactic peptides and catalysis of reactive tion of as many as 200 different genes, including TNF-α, IL-1β and IL-6.
oxygen metabolite generation). The proinflammatory cytokines and their activities are counter-
balanced by a wide variety of “antiinflammatory” cytokines, including
IL-4, IL-10, IL-11, IL-13, TGFβ, IL-1ra, and several soluble cytokine
CYTOKINES AND CHEMOKINES receptors. 2,3,7 IL-4, a 20-kDa peptide produced by CD4 Th2 cells, inhib-
Cytokines are proteins that exhibit a variety of proinflammatory and its IL-1β synthesis and induces IL-1ra (IL-1 receptor antagonist). Sol-
antiinflammatory effects. They are produced by many cell types and uble IL-1ra binds IL-1β (and IL-1α), preventing their binding to IL-1
modulate the function of other cell types. Individual cells may produce receptors. IL-10 is also secreted by CD4 Th2 cells (and regulatory T
many different cytokines, and an individual cytokine may exert a wide cells, monocytes, and macrophages). Acting through its cognate recep-
variety of effects; they are pleiotropic. 2,3,6 In addition to their important tor, IL-10 suppresses the expression of proinflammatory cytokines,
roles in regulating various aspects of the immune response (e.g., lym- adhesion molecules, chemokines, and cell-surface activation molecules
phocyte activation, proliferation, and differentiation), many cytokines of neutrophils, monocytes, macrophages, and T lymphocytes. IL-10
7
participate in innate immunity (e.g., TNF-α, IL-1β, IL-6, type I inter- also induces the shedding of TNF-α receptors, which then function as
ferons), mediate the acute-phase response (TNF-α, IL1β, IL-6), activate soluble TNF-α antagonists. IL-11, IL-13, and TGFβ also each exert a set
inflammatory cells (e.g., IFN-γ) and participate in hematopoiesis (e.g., of activities that counter the proinflammatory actions of TNF-α, IL-1β,
IL-3, granulocyte-monocyte colony-stimulating factor, granulocyte and IL-6. Recognition of the many counterbalancing actions between
colony-stimulating factor, macrophage colony-stimulating factor). proinflammatory and antiinflammatory cytokines has led to the con-
2,3
Among the most thoroughly characterized cytokines are TNF-α and cept of “proinflammatory–antiinflammatory cytokine balance.” This
IL-1β, which are structurally dissimilar but share many biologic activi- concept is the basis for rational therapeutic strategies to manipulate or
ties and can function as autocrine, paracrine and endocrine mediators “reset” this balance.
of inflammation (Table 19–4). TNF-α and IL-1β are produced by var- TNF-α, IL-1β, and IL-6 are key proximate mediators of the “acute-
2,3
ious cell types and are pleiotropic. Particularly important functions in phase response.” Stimuli such as bacterial endotoxin (lipopolysaccha-
inflammation include endothelial, leukocyte and fibroblast activation. ride), exotoxins, immune complexes and physical stimuli (e.g., heat or

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