Biomedical Engineering Reference
In-Depth Information
B transcriptional activity
[77,78], apparently at a level secondary to the regulation of IKK [77].
An essential role for NF-
associated with inflammation — are known to stimulate NF-
κ
B in promoting inflammation may be to promote
survival of invading inflammatory cells. Thus, Cheah and colleagues [79] found
NF-
κ
B to be activated in inflammatory neutrophils from premature infants. This
activation was inversely correlated with proapoptotic caspase-3 activation. Addition-
ally, others have shown that the resolution of sepsis-associated neutrophil-mediated
inflammation occurs through apoptosis, and suppression of NF-
κ
κ
B activation in these
cells promotes apoptosis [80]. NF-
B inhibitors increase apoptosis in neutrophils
and eosinophils, causing these cells to undergo TNF-induced apoptosis. In these
cells, evidence has been presented that the production of the prostaglandin PGD2
suppresses NF-
κ
B func-
tions early in inflammation to promote inflammation, partly through its ability to
suppress apoptosis. Later, in the resolution phase, NF-
κ
B activation in late stages of inflammation [81]. Thus, NF-
κ
B may function to induce its
own inhibition through the production of distinct prostaglandins.
The gut maintains a physiological level of inflammation in response to endog-
enous bacterial flora. The presence of pathogenic bacteria is typically sufficient to
activate an inflammatory response that appears to be mediated by NF-
κ
B. For
example, flagellin, the structural component of bacterial flagella, activates NF-
κ
B
through TLR5 [82]. These innate mucosal events are essential for combating gut
infections. Recent evidence indicates that certain nonpathogenic bacteria can block
NF-
κ
κ
B activation; for example, nonvirulent Salmonella strains inhibit NF-
κ
B acti-
vation in intestinal epithelial cells through a mechanism that prevents I
B ubiquit-
ination and subsequent degradation [83]. Another group [84] showed that a com-
mensal bacterium,
B. thetaiotamicron
, suppresses inflammation by promoting an
association between PPAR
κ
and p65, leading to p65/RelA export from the nucleus.
These reports suggest that prokaryotic determinants are responsible for tolerance of
the gastrointestinal mucosa to inflammatory signals. Additionally, it suggests that
NF-
γ
B is a major mediator of the inflammatory response.
Naturally occurring antiinflammatory molecules have been shown to inhibit
κ
NF-
B. In this way, the antiinflammatory cyclopentonone prostaglandin 15d-PGJ
2
,
the natural ligand for PPAR
κ
γ
, can block NF-
κ
B activation. This prostaglandin
appears to suppress NF-
α
and through direct inhibition of IKK [85,86]. We reported previously that the anti-
inflammatory protein IL-10 can suppress NF-
κ
B activation both through the induced upregulation of I
κ
B
B through a mechanism associated
with reduced or delayed IKK activity [87]. Additionally, antiinflammatory mecha-
nisms associated with NO production (see above)
have been attributed to the ability
κ
Inhibition of NF-
κ
B in bone marrow-derived macrophages by expression of
superrepressor I
converted these cells from highly proinflammatory to strongly
antiinflammatory [89]. Macrophages were reoriented from expression of iNOS, TNF,
and IL-12 to express high levels of IL-10. These cells, when injected in association
with a glomerulonephritis model, strongly reduced renal injury and suppressed the
inflammatory milieu. These data indicate that NF-
κ
B
α
B promotes the proinflammatory
phenotype in macrophages and actively suppresses the antiinflammatory phenotype.
κ
