Relationship of platelet-activating factor metabolism in dendritic cells to IgG2 production

This research was prompted by our studies of Localized Aggressive Periodontitis (LAgP), a disease that is associated with high IgG2 production and a propensity of monocytes to differentiate into MDDC. Although Macrophages (M&phis;) and Monocyte-Derived Dendritic Cells (MDDC) come from a common precursor, they are distinct cell types. In this study we compared the two cell types with respect to the metabolism of Platelet-Activating Factor (PAF), a biologically active lipid mediator. As the IgG2 antibody response is dependent on PAF and MDDC selectively induce IgG2 production we predicted that PAF levels would be higher in MDDC than in M&phis;. Both M&phis; 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 M&phis; 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, M&phis; did not respond in this manner. Moreover, both PAF and PGE₂ can modulate the functioning of B cells. Therefore, we hypothesized that PAF and PGE₂ might have direct effects on B cells and might induce IgG2 production by promoting IgG2 class switch recombination (CSR) or the differentiation of IgG2 producing B cells. Although PAF and PGE₂ induce IgG2 production by human PBL, their effects are not directly on B cells as they do not induce IgG2 CSR or the differentiation of IgG2 producing cells. These data suggest that PAF and PGE₂ promote IgG2 production by stimulating accessory cells instead of B cells. We also demonstrate that IFNγ synergizes with IL-4 to induce IgG2 CSR. Since both lipid mediators can induce this cytokine, the effects of PAF and PGE₂ on IgG2 production may be mediated by IFNγ. Together, these data indicate that PAF metabolism may regulate the IgG2 response by regulating the accessory activity of MDDC.