380
Antigen Presenting Cells (APCs)
is accomplished in three ways: (1) T
H1
cells secrete the hematopoietic growth
factors IL-3 and GM-CSF (granulocytes-
macrophage-colony-stimulating
factor),
which stimulate generation of monocytes
and neutrophils in the bone marrow;
(2) T
H1
cells at sites of infection secrete
TNF-
α
and
TNF-
β
which
promote
diapedesis of monocytes in endothelia;
(3) T
H1
cells in inflamed tissues secrete
the
chemokine
MCP-1
(macrophage
chemotactic
protein),
which
attracts
macrophages.
8.4.2
Tissue Remodeling
Macrophages, in particular activated ones,
can secrete a number of proteins not
directly related to their functions in in-
nate or acquired immune responses but
leading to local changes in the architec-
ture of the tissue where macrophages are
residing. Macrophages are the principal
source of angiogenic factors, for example,
vascular-endothelial growth factor (VEGF),
factors that stimulate ±broblast prolifera-
tion, for example, platelet-derived growth
factor (PDGF), and factors that regu-
late connective tissue biosynthesis, for
example, transforming growth factor-
β
(TGF-
β
). Beyond that, unlike neutrophils,
macrophages secrete proteases belonging
to the matrix-metalloproteinases that de-
grade extracellular matrix proteins. At the
same time, they activate ±broblasts to syn-
thesize new matrix proteins. In settings of
prolonged activation, macrophages even
mediate tissue ±brosis.
8.5
Deactivated and Alternatively Activated
Macrophages
In order to minimize local tissue dam-
age and energy consumption, macrophage
activation needs to be downregulated at a
certain point of time. One way of achieving
this is by T
H1
cells regulating the half-life
of their mRNA encoding IFN-
γ
.A
c
t
i
v
a
-
tion of T
H1
cells through engaging MHC
class II–peptide complexes, CD80/CD86,
and CD40 on the macrophage surface
induces a new protein that promotes cy-
tokine mRNA degradation, including IFN-
γ
mRNA. Another regulatory mechanism
is the production of deactivating glucocor-
ticoids and cytokines, such as TGF-
β
,IL-4,
IL-10, and IL-13, especially by T
H2
cells.
Thus, the induction of differentiation of
T
H2
cells is a critical pathway for con-
trolling the effector functions of activated
macrophages.
More recently, however, IL-4 and gluco-
corticoids were found to induce increased
expression of the MR and to enhance
the capacity for endocytosis and antigen
presentation of macrophages. This ar-
gues against mere deactivation and gave
rise to the concept of alternative activa-
tion of macrophages. Alveolar and pla-
cental macrophages are typical examples.
They express certain molecules selectively,
such as the chemokine AMAC-1 (alter-
native macrophage activation-associated
chemokine-1). AMAC-1 is related to MIP-
1
α
, induced by classical macrophage ac-
tivators, such as LPS, and inhibited by
IL-4. Conversely, AMAC-1 is speci±cally
inducedbyIL-4andIL-10andinhibitedby
IFN-
γ
. AMAC-1 is supposed to facilitate a
downregulatory T
H2
circuit in inflamma-
tory reactions. Moreover, tumors secreting
IL-10 and TGF-
β
may systemically and
locally induce alternative macrophage acti-
vation. These macrophages may facilitate
immune escape mechanisms, observed in
malignant tumors, by secretion of growth
and angiogenic factors supporting en-
hanced vascularization and nutrition of
thetumo
r
.Mo
reins
igh
tin
tothero
leo
f
alternatively activated APCs is required.