Biomedical Engineering Reference
In-Depth Information
Proinflammatory Functions of NF-
κ
B Include Transcription of:
-iNOS*
-Cytokines
-Chemokines
-MMPs
-Antiapoptotic factors
-Cox2*
Antiinflammatory Functions of NF-
κ
B Include Transcription of
:
-Cox2*
-iNOS*
*Cox2 and iNOS gene products can function in both proinflammatory
and antiinflammatory pathways.
FIGURE 8.5
Pro- and antiinflammatory effects of NF-
κ
B.
8.2 ROLE OF NF-
B IN MEDIATING PRO- AND
ANTIINFLAMMATORY MECHANISMS
κ
8.2.1 NF-
B I
S
A
K
EY
M
EDIATOR
OF
THE
I
NFLAMMATORY
R
ESPONSE
AND
OF
I
NFLAMMATORY
D
ISEASES
κ
Previous studies of mice genetically deficient in components of the NF-
B pathway
demonstrate that these proteins play key roles in promoting the inflammatory response
(
Chapters 6
and
7
). For example, Alcamo and colleagues [71] showed that p65/RelA
is critical for leukocyte recruitment during inflammation. c-Rel has a role in promoting
hematopoietic cell survival and production of mediators that maintain the inflammatory
response. Gerondakis and colleagues [72] showed that c-Rel has both positive and
negative regulatory functions in different macrophage populations, and other studies
indicate that c-Rel and p65 serve redundant functions in controlling the differentiation
and survival of committed progenitors in multiple hemopoietic cell lineages [73].
NF-
κ
B activation in models of inflammation indicates a role for this transcription
factor in promoting inflammation through upregulation of COX-2 and iNOS and
κ
B inhibitors given early in
the rat carrageenin pleurisy model suppressed the inflammatory response [74]. How-
ever, when given later in the model, these inhibitors led to sustained inflammation (see
comments in
Section 8.2.2
regarding this point). The role of NF-
κ
B in promoting the
transcription of key inflammatory genes such as IL-8, COX-2, iNOS, several chemok-
ines, and MCP-1 is consistent with the role of this transcription factor in regulating
the cellular hierarchy that promotes the inflammatory response (see Figure 8.5).
The production of certain MMPs in monocytes, which promote migration of these
inflammatory cells as well as disease-related connective tissue destruction, is controlled
through NF-
κ
B activation [75]. This same group has provided evidence that the pro-
duction of MMP-9 in activated monocytes is controlled through a PI3K/Akt/IKK
κ
α
/
NF-
κ
B pathway [76]. Prostaglandins such as PGE
2
and leukotrienes — molecules
