Tissue Development, Repair, and Remodeling - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 712

inflammation site, phagocytes release inflammatory cytokines, such as interleukin-1
and -6 as well as tumor-necrosis factor- α .

not only stimulate adhesion molecules, but also
activate macrophages and initiate production of growth factors required for healing
and inflammatory mediators. These cytokines induce the production of acute-phase
proteins by the liver, such as C-reactive protein and mannan-binding lectin, and
increase hematopoiesis.
In vascular inflammation, various pro-inflammatory factors activate resident
vascular smooth myocytes, fibroblasts, and endothelial cells via the NF

Cytokines IL1 and TNF α

Btran-
scription factor, such as TNFSF1, TNFSF5, angiotensin-2, and oxidized LDLs.
Circulating monocytes enter the vessel wall from the arterial lumen or vaso
vasorum. Monocyte activation is controlled by local IL6 production. Interleukin-
6 is a pleiotropic glycoprotein secreted by diverse vascular cell types, such as
macrophages, lymphocytes, fibroblasts, and endothelial and smooth muscle cells.
Production of IL6 is upregulated by angiotensin-2, cytokines, and reactive oxygen
species [ 1446 ]. Interleukin-6 signals via the IL6 receptor and Ras-ERK and JaK-
STAT pathways. 41

κ

11.5.6.3 Tumor-Necrosis Factor

Tumor-necrosis factor binds to 2 distinct receptors: (1) TNFR1, i.e., receptor
subunits P55 TNFR1 and P60 TNFR1 that are constitutively expressed by most
cell types and (2) TNFR2, i.e., receptor subunits P75 TNFR2 and P80 TNFR2 ,the
expression of which is induced mainly in immune and endothelial cells.
Both receptors can cooperate to transduce signals, as they activate MAPK
enzymes, NF B, and AP1 transcriptional activator. Tumor-necrosis factor not only

quickly activates inflammation genes via NF

κ

κ B and MAPKs, but also induces

delayed responses.
High-affinity TNFR1 lacks intrinsic kinase activity. Binding of TNF to TNFR1

provokes TNFR1 trimerization and recruitment of adaptors and signaling mediators,
such as TNFR-associated factors TRAF2, TRAF5, and TRAF6, receptor-interacting
protein kinase (RIPK), mitogen-activated protein kinase kinase kinases MAP3K3
and MAP3K7, that build an inducible submembranous complex.

α

41 In normal conditions, vascular endothelial and smooth muscle cells do not express high IL6R
levels. Trans-signaling by soluble IL6R α that results from ectodomain shedding by adamlysin
ADAM10 and ADAM17 raises expression of IL6R in vascular endothelial and smooth muscle
cells. Enzyme JaK1 phosphorylates STAT1 and STAT3 and causes homo- and heterodimerization
and nuclear translocation for gene transcription. Activity of STAT factor is also modulated by
acetylation. Once it resides in the nucleus, STAT3 associates with P300 and CBP coactivators.
Activated nuclear STAT3 controls the expression of genes for tissue remodeling (collagen and
fibronectin), cell growth (cyclin-D1 and MyC factor), in addition to mediators (angiotensinogen,
C-reactive protein, and

γ

-fibrinogen) [ 1446 ].