Differential Expression of Platelet-Activating Factor Acetylhydrolase in Macrophages and Monocyte-Derived Dendritic Cells

Abstract

Although macrophages (Mφ) and monocyte-derived dendritic cells (MDDC) come from a common precursor, they are distinct cell types. This report compares the two cell types with respect to the metabolism of platelet-activating factor (PAF), a biologically active lipid mediator. These experiments were prompted by our studies of localized juvenile periodontitis, a disease associated with high IgG2 production and a propensity of monocytes to differentiate into MDDC. As the IgG2 Ab response is dependent on PAF, and MDDC selectively induce IgG2 production, we predicted that PAF levels would be higher in MDDC than in Mφ. To test this hypothesis, human MDDC were prepared by treating adherent monocytes with IL-4 and GM-CSF, and Mφ were produced by culture in M-CSF. Both Mφ and MDDC synthesized PAF; however, MDDC accumulated significantly more of this lipid. We considered the possibility that PAF accumulation in MDDC might result from reduced turnover due to lower levels of PAF acetylhydrolase (PAFAH), the enzyme that catabolizes PAF. Although PAFAH increased when monocytes differentiated into either cell type, MDDC contained significantly less PAFAH than did Mφ and secreted almost no PAFAH activity. The reduced levels of PAFAH in MDDC could be attributed to lower levels of expression of the enzyme in MDDC and allowed these cells to produce PGE2 in response to exogenous PAF. In contrast, Mφ did not respond in this manner. Together, these data indicate that PAF metabolism may impinge on regulation of the immune response by regulating the accessory activity of MDDC.

Modulation of oxidative stress, inflammation, and atherosclerosis by lipoprotein-associated phospholipase A2

“…We found that IFN-␥ , which has been implicated as a promoter of foam cell formation and an inducer of M1 pro-infl ammatory phenotypes ( 47 ), decreased expression of Lp-PLA 2 at the transcriptional level ( 48 ). Conversely, M-CSF, which induces an M2-like, anti-infl ammatory phenotype, increased monocyte Lp-PLA 2 expression to a much higher extent compared with the M1-inducer GM-CSF ( 49 ). However, Ferguson and coworkers reported modest increases or no changes in Lp-PLA 2 mRNA levels in M1 and M2 macrophages, respectively, using different induction strategies ( 44 ).…”

Altered lipoprotein subclass distribution and PAF-AH activity in subjects with generalized aggressive periodontitis

“…Recent observations indicate that the monocytes of subjects with localized aggressive periodontitis (LAgP) have a propensity to differentiate into dendritic cells, which synthesize and secrete much less PAF-AH than macrophages (53). This raises the possibility that, compared with controls, LDLs from subjects with periodontitis may contain less PAF-AH activity and, as a result, lack the protective, antiatherogenic influence that this enzyme may have.…”

“…Although PAF-AH expression increases when monocytes differentiate into macrophages or dendritic cells (53,70), dendritic cells express much lower levels of the enzyme than macrophages. We have shown previously that, in culture, monocyte-derived dendritic cells of subjects with LAgP (then called localized juvenile periodontitis) synthesize and secrete much less PAF-AH activity than monocytederived macrophages (53).…”

The p38 MAPK Pathway Mediates Transcriptional Activation of the Plasma Platelet-activating Factor Acetylhydrolase Gene in Macrophages Stimulated with Lipopolysaccharide

“…For example, the kinetics and magnitude of PAF AH expression are different in primary macrophage populations that differ in CD14 and CD16 expression levels. 3 Moreover, differentiation of monocytes into dendritic cells results in significantly lower levels of intracellular and secreted PAF AH activity compared with macrophages (49). A key contribution of the present study is the utilization of a murine model system that mimics in vivo responses in cells that are not terminally differentiated and, thus, potentially recapitulates events that occur when monocytic cells are recruited and induced to differentiate in inflamed tissues in vivo.…”