Biomedical Engineering Reference
In-Depth Information
Activated circulating and tissue-resident monocytes and macrophages are the
main producers of TNF monokine in innate immune responses and in chronic
inflammatory diseases. This cytokine generates an autocrine loop characterized by
low, sustained production of interferon-
β
. Whereas TLRs prime massive, rapid,
transient Ifn
β
production via interferon-regulatory factors IRF3 or IRF7, TNF-
mediated Ifn
-mediated autocrine loop sustains the
expression of inflammation genes and causes delayed expression of interferon-
response genes that encode transcription factors STAT1 and IRF7 [
1459
]. This
autocrine regulation of gene expression depends on IRF1 and synergy between
produced interferon and activated NF
β
acts via IRF1. Interferon-
β
B factor. The latter enhance macrophage
response to cytokines and Toll-like receptors. Monokine TNF thus activates a
feedback loop, but avoids the toxicity of high interferon production induced by
stimulated Toll-like receptors.
Tumor-necrosis factor signals via the canonical NF
κ
B pathway that activates the
IKK signalosome
(Sect.
11.5.6.4
).
42
It modulates cellular responses via the MAPK
and NF
κ
B signaling pathways to activate gene transcription. Another regulatory
mechanism of TNF-dependent MAPK signaling exists [
1460
].
Non-receptor protein Tyr phosphatase PTPn2 is involved in hematopoiesis
and impedes inflammation. Phosphatase PTPn2 selectively regulates TNF-MAPK
signaling, suppressing the activation of MAPK enzymes by tumor-necrosis factor,
without acting on the NF
κ
B pathway. It interacts with adaptor TRAF2 and
inactivates SRC family kinase, modulating TNF-mediated inflammation. Besides,
TNF is a potent inducer of interleukin-6. Deficiency of PTPn2 leads to: (1) enhanced
signaling by ERK1 and ERK2, but not P38MAPK, and (2) higher IL6 levels.
Kinases of the SRC family are involved in the elevated TNF-MAPK signaling
observed in PTPn2-deficient cells. Phosphatase PTPn2 selectively regulates the
TNF-MAPK pathway by inhibiting SRC family kinases. In addition, the control by
PTPn2 of the activation of extracellular signal-regulated protein kinases ERK1 and
ERK2 induced by SRC family kinases in hematopoietic cells appears to be specific
to cell type.
κ
11.5.6.4
Nuclear Factor-
κ
B
Nuclear
factor-
κ
B
factors
operate
in
immune
responses
and
inflammation.
Category-1 NF
κ
B heterodimers, i.e., NF
κ
B1 (P105
NF
precursor monomer
κ
B
processed to generate P50
NF
dimer) and NF
κ
B2 (P100
NF
precursor mono-
κ
B
κ
B
mer processed to generate P52
NF
dimer), can associate with transcriptionally
κ
B
active category-2 NF
B3), or RelB;
Vol. 4 - Chap. 10. Other Major Signaling Mediators). Subunits Rel, RelA, and
RelB have a transactivating domain (TAD) to trigger transcription in synergy with
recruited transcriptional coactivators.
κ
B proteins, i.e., Rel, RelA (P65
NF
or NF
κ
κ
B
42
This kinase complex contains 2 kinases IKK
α
β
γ
and IKK
and the regulatory IKK
subunit.
Search WWH ::
Custom Search