Biomedical Engineering Reference
In-Depth Information
Cox2 Transcription
NF-
B
κ
Cox2/prostaglandin synthase
NF-
κ
B
NF-
κ
B
PGE2
PGJ2
FIGURE 8.3
NF-
κ
B-dependent transcription of COX-2 can have pro- and antiinflammatory
outcomes.
through PGD
2
receptors and through interaction with certain cellular targets [24]
(see Figure 8.3, and see
Section 8.2.2
).
While macrophages clearly are mediators of the proinflammatory phenotype,
there is evidence that these cells contribute to resolution of inflammation (see
Figure
8.2
). Suspicion that macrophages might function in inflammatory resolution origi-
nated from the observation that the degree of macrophage infiltration at sites of
inflammation does not always correlate with severity of injury [25]. Macrophages
secrete high levels of the antiinflammatory cytokine IL-10 late in the inflammatory
antiinflammatory molecules such as IL-4 and IL-10 into the kidney reduces renal
inflammation [27]. Consistent with this finding, IL-10 was shown to be involved in
both the onset and the resolution of inflammation in a mouse model of asthma [28].
In addition, observations of inflammation in skin and lung also demonstrate the
importance of macrophages in the resolution of injury and the repair of tissue [29,30].
Apoptosis of inflammatory cells is crucial in the resolution of inflammation
because of the high levels of recruitment and expansion of leukocyte populations
that occurs during the inflammatory process [3,31]. Thus, the resulting clearance of
apoptosed leukocytes by macrophages is important for the resolution of inflammation
[31]. Consistent with this, and as discussed above, the ability of organisms to resolve
inflammation appears to be significantly controlled by the production of IL-10 and
TGF
, derived from epithelial and regulatory T cells [32,33]. In this regard, it has
been postulated that defects in inflammatory cell apoptosis contribute to the patho-
genesis of inflammatory diseases.
Endogenous glucocorticoids are well-known antiinflammatory mediators, func-
tioning through their ability to bind glucocorticoid receptors and to modulate a
variety of pathways (reviewed in [34]). As discussed in Section 8.2.1, activated
glucocorticoid receptors can function to suppress NF-
β
B activity. Additionally, glu-
cocorticoids can induce the expression of genes encoding proteins with antiinflam-
matory functions [34]. These gene targets include annexin 1/lipocortin 1, which can
inhibit the production of prostaglandins (see [
35
]), and lipoxins, which suppress
neutrophil and eosinophil chemotaxis [35,36]. Lipoxins also promote the ability of
macrophages to clear apoptotic cells [37].
κ
