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ZSA TNFa in lokale en systemische ontsteking- twee gezichten van hetzelfde cytokine
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ZSA TNFa in lokale en systemische ontsteking- twee gezichten van hetzelfde cytokine
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ZSA TNFa in lokale ensystemische ontsteking:
twee gezichten van
hetzelfde cytokine
Paragraaf 3-4 p. 53-54: Activation of resident macrophages induces a state
of inflammation at sites of infection
Cytokines are small soluble proteins used as a means of communication between
cells. In response to an external stimulus such as infection, one type of cell secretes a
cytokine that binds to a specific cytokine receptor on the surface of another type of
cell. Binding of cytokine to the receptor induces intracellular signals that change the
behavior of the second cell. In general, cytokines are short-lived molecules that exert
their influence within a short distance from the cell that made them, and in some in-
stances the cytokine-secreting cell makes direct contact with the cell it will influence.
These properties of cytokines ensure that the immune response, which inevitably
causes collateral damage to tissues, is restricted to where it is needed.
When infection has been detected in a tissue, the resident macrophages be-
come activated to recruit other cells to the infected tissue by secreting several cy-
tokines. Prominent among these are interleukin-1β (IL-1β), interleukin-6 (IL-6),
interleukin-12 (IL-12), CXCL8, and tumor necrosis factor-α (TNF-α). Collec-
tively, these cytokines are called inflammatory cytokines, or pro-inflammatory
cytokines, because their combined effect is to create a state of inflammation in the
infected tissue. Inflammation causes the infected tissue to swell and become red,
painful, and hot. Although these are the symptoms we associate with infections and
wounds, they are actually caused by the immune response to those insults. Inflamma-
tion is a familiar and universal experience for us all, but especially for children with
their frequent coughs and colds as well as daily bangs, bumps, and scrapes. The con-
tributions of the five inflammatory cytokines will be summarized here and expanded
upon in subsequent sections.
In general, the cells of the immune system have some limited access to healthy
tissue, but for neutrophils—the destructive phagocytes that do the hardest work in
clearing infection—all access is denied. A major task of the inflammatory cytokines is
to reverse this situation. When that happens, not only are neutrophils able to migrate
from blood to the infected tissue, but they are actively encouraged to do so and
guided to their destination. Cytokines IL-1β and TNF-α induce changes to the endothe-
lial cells of blood vessels in the infected tissue that allow fluid and cells to leave the
blood. This involves an increase in the diameter of the blood vessels (dilation), with a
commensurate decrease in the blood flow. Cytokine-induced changes to the surface
molecules of the vascular endothelium instruct neutrophils and other leukocytes to
stop and exit from the blood. CXCL8 is a chemoattractant cytokine, or chemokine,
which attracts neutrophils away from blood and toward the infected area where
, macrophages are secreting inflammatory cytokines. This is achieved by a chemokine
receptor on neutrophils that binds CXCL8, which then signals the cells to move up the
concentration gradient of the chemokine.
Monocytes (macrophage precursors) and NK cells are also recruited to the in-
fected tissue, although in much smaller numbers than neutrophils. Cytokine IL-12 in-
duces NK cells to proliferate and secrete cytokines that sustain macrophage activa-
tion. Monocytes recruited from the blood mature into macrophages in the infected tis-
sue, adding to the resident population. As the inflammation develops, a major task of
these macrophages is the phagocytosis and disposal of the immense number of neu-
trophils that die in the cause of containing infection. The increased passage of fluid
and cells from the blood into the surrounding connective tissues causes the character-
istic swelling, reddening, and pain that is associated with inflammation. The increase
in temperature is a consequence of the cytokine IL-6, which acts on local muscle and
fat cells, causing them to adjust their metabolism and generate more heat.
Paragraaf 3-13: Toll-like receptors sense the presence of the four main
groups of pathogenic microorganisms
In previous sections we saw how TLR4 recognizes bacterial products, and how it sig-
nals macrophages to respond to bacterial infection. Complementing this function of
TLR4, other members of the family of Toll-like receptors recognize the presence of vi-
ral, fungal, and parasitic infections. The Toll- like receptors form two distinctive groups
in terms of their function. Receptors in the first group, which includes TLR4, are lo-
cated on the plasma membrane and recognize carbohydrate, lipid, and protein struc-
tures on the outer surfaces of pathogens. By contrast, receptors in the second group
are located inside the cell and in the membranes of endosomes, and recognize fea-
tures that distinguish the nucleic acids of pathogens from the nucleic acids of human
cells. For example, TLR3 recognizes double-stranded RNA, which characterizes many
viral infections, and TLR9 detects the unmethylated CpG nucleotide motifs that are
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