C h a p t e r 3
Inflammation, the Inflammatory Response, and Fever
59
factor-induced platelet aggregation and degranulation
at the site of injury enhances serotonin release, thereby
causing changes in vascular permeability. It also enhances
leukocyte adhesion, chemotaxis, and leukocyte degranu-
lation and stimulates the synthesis of other inflammatory
mediators, especially the prostaglandins.
Cytokines and Chemokines.
Cytokines are low-
molecular-weight proteins that are important cellular
messengers. They modulate the function of cells by
paracrine and autocrine mechanisms to cause responses
in neighboring cells and the cells that produced the cyto-
kine, respectively. They are produced by many cell types,
including activated macrophages and lymphocytes,
endothelial cells, epithelial cells, and fibroblasts.
1,2,18
Although well known for their role in adaptive immune
responses, these proteins also play important roles in
both acute and chronic inflammation.
Tumor necrosis factor-
α
(TNF-
α
) and interleukin-1
(IL-1) are two of the major cytokines that mediate
inflammation. The major cellular source of TNF-
α
and
IL-1 is activated macrophages (Fig. 3-5). Interleukin-1
is also produced by many other cell types, including
neutrophils, endothelial cells, and epithelial cells (e.g.,
keratinocytes). The secretion of TNF-
α
and IL-1 can
be stimulated by bacterial toxins, immune cells, injury,
and a variety of inflammatory stimuli. TNF-
α
and IL-1
induce endothelial cells to express adhesion molecules
and release other cytokines, chemokines, and reactive
oxygen species. Tumor necrosis factor-
α
induces priming
and aggregation of neutrophils, leading to augmented
responses of these cells to other mediators. Interleukin-1
and TNF-
α
are also mediators of the acute-phase
responses associated with infection or injury. Features of
these systemic responses include fever, hypotension and
increased heart rate, anorexia, release of neutrophils
into the circulation, and increased levels of corticoste-
roid hormones.
Chemotactic cytokines, or
chemokines
, are a family of
small proteins that act primarily as chemoattractants that
both recruit and direct the migration of inflammatory
and immune cells
20
(see Chapter 15). Chemokines gener-
ate a chemotactic gradient by binding to proteoglycans
on the surface of endothelial cells or in the extracellu-
lar matrix.
20
As a result, high concentrations of chemo-
kines persist at sites of tissue injury or infection. Two
classes of chemokines have been identified: inflamma-
tory chemokines and homing chemokines. Inflammatory
chemokines are produced in response to bacterial toxins
and inflammatory cytokines (i.e., IL-1, TNF-
α
). These
chemokines recruit leukocytes during an inflammatory
response. Homing chemokines are constantly produced,
with the genes that control their production being
up-regulated during inflammatory reactions.
Nitric Oxide.
Nitric oxide (NO), which is produced by
a variety of cells, plays multiple roles in inflammation,
including relaxation of vascular smooth muscle; antag-
onism of platelet adhesion, aggregation, and degranu-
lation; and as regulator of leukocyte recruitment.
2
Blocking of NO production under normal conditions
promotes leukocyte rolling and adhesion to postcapillary
venules and delivery of exogenous NO reduces leuko-
cyte recruitment. Thus, production of NO appears to be
an endogenous compensatory mechanism that reduces
the cellular phase of inflammation. Impaired production
of NO by vascular endothelial cells is implicated in the
inflammatory changes that occur with atherosclerosis
(see Chapter 18). Nitric oxide and its derivatives also
have antimicrobial actions, and thus NO is also a host
mediator against infection.
Reactive Oxygen Species.
Reactive oxygen species
may be released extracellularly from leukocytes after
exposure to microbes, cytokines, and immune com-
plexes, or in the phagocytic process that occurs dur-
ing the cellular phase of the inflammatory process. The
superoxide radical, hydrogen peroxide, and hydroxyl
radical (discussed in Chapter 2) are the major species
produced within the cell. These species can combine
with NO to form other reactive nitrogen intermedi-
ates. Extracellular release of low levels of these potent
mediators can increase the expression of cytokines and
endothelial adhesion molecules, amplifying the cascade
that elicits the inflammatory process,
2
and increase cell
Gram-negative
bacteria
LPS
IFN-
γ
Macrophage
T cells
TNF-
α
, IL-1
ENDOTHELIAL
CELLS
Adhesion molecules
Cytokines
Eicosanoids
Chemokines
Oxygen radicals
Aggregation
Priming
Fever
Anorexia
Hypotension
Increased heart rate
Corticosteroid and
ACTH release
NEUTROPHILS
ACUTE-PHASE
RESPONSE
FIGURE 3-5.
Central role of interleukin (IL)-1 and tumor
necrosis factor (TNF)-
α
in inflammation. Lipopolysaccharide
(LPS) and interferon (IFN)-
γ
activate macrophages to release
inflammatory cytokines, principally IL-1 andTNF-
α
, responsible
for directing both local and systemic inflammatory responses.
ACTH, adrenocorticotrophic hormone. (From Murphy
HS. Inflammation. In: Rubin R, Strayer DS, eds. Rubin’s
Pathology: Clinicopathologic Foundations of Medicine. 6th ed.
Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams &
Wilkins; 2012:60.)
