76 SECTION ICellular & Molecular Basis for Medical Physiology
is characterized by redness, swelling, tenderness, and pain.
Elsewhere, it is a key component of asthma, ulcerative colitis,
and many other diseases.
Evidence is accumulating that a transcription factor,
nuclear factor-κB, plays a key role in the inflammatory
response. NF-κB is a heterodimer that normally exists in the
cytoplasm of cells bound to IκBα, which renders it inactive.
Stimuli such as cytokines, viruses, and oxidants separate NF-
κB from IκBα, which is then degraded. NF-κB moves to the
nucleus, where it binds to the DNA of the genes for numerous
inflammatory mediators, resulting in their increased produc-
tion and secretion. Glucocorticoids inhibit the activation of
NF-κB by increasing the production of IκBα, and this is prob-
ably the main basis of their anti-inflammatory action (see
Chapter 22).
SYSTEMIC RESPONSE TO INJURY
Cytokines produced in response to inflammation and other
injuries also produce systemic responses. These include alter-
ations in plasma acute phase proteins, defined as proteins
whose concentration is increased or decreased by at least 25%
following injury. Many of the proteins are of hepatic origin. A
number of them are shown in Figure 3–14. The causes of the
changes in concentration are incompletely understood, but it
can be said that many of the changes make homeostatic sense.
Thus, for example, an increase in C-reactive protein activates
monocytes and causes further production of cytokines. Other
changes that occur in response to injury include somnolence,
negative nitrogen balance, and fever.
WOUND HEALING
When tissue is damaged, platelets adhere to exposed matrix via
integrins that bind to collagen and laminin (Figure 3–13).
Blood coagulation produces thrombin, which promotes platelet
aggregation and granule release. The platelet granules generate
an inflammatory response. White blood cells are attracted by
selectins and bind to integrins on endothelial cells, leading to
their extravasation through the blood vessel walls. Cytokines re-
leased by the white blood cells and platelets up-regulate inte-
grins on macrophages, which migrate to the area of injury, and
on fibroblasts and epithelial cells, which mediate wound healing
FIGURE 3–11 Action of cyclosporine (CsA) and tacrolimus
(TCL) in lymphocytes. BP, binding protein; CAM, calmodulin.
T cell receptor
Ca^2 +
CAM
Calcineurin
TCLBP
CsABP
P
NF-AT
IL-2 gene
activation
Nucleus
FIGURE 3–12 Sites of congenital blockade of B and T lymphocyte maturation in various immunodeficiency states. SCID, severe
combined immune deficiency. (Modified from Rosen FS, Cooper MD, Wedgwood RJP: The primary immunodeficiencies. N Engl J Med 1995;333:431.)
Pluripotent
stem cell
Lymphoid
progenitor
Autosomal
recessive SCID
BONE
MARROW
pre-B cell
THYMUS
Immature
T cell
X-linked SCID
X-linked
agamma-
globulinemia
B cell
Hyper-IgM
syndrome
IgM IgG IgA IgE
MHC class I
deficiency
MHC class II
deficiency
CD8
cell
CD4
cell