Prostaglandin E2-mediated regulation of immunoglobulin G2 via interferon gamma.

BACKGROUND

Patients with localized aggressive periodontitis (LAgP) produce elevated levels of IgG2 both in vivo and in vitro. Responses to the periodontitis-associated pathogens Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis are dominated by IgG2, and these IgG2 responses are associated with reduced extent and severity of disease. Little is known about regulation of the IgG2 subclass, although prostaglandin E2 (PGE2) (a mediator known to polarize responses toward Th-2) and interferon (IFN)-gamma (a Th-1 mediator) both promote IgG2 production. This unusual relationship prompted the hypothesis that, in certain circumstances, PGE2 enhances rather than inhibits IFN-gamma production.

METHODS

To test this hypothesis, indomethacin (IND)-treated peripheral blood mononuclear cell (PBL) cultures from healthy volunteers were stimulated with pokeweed mitogen (PWM), and the cultures were manipulated by adding PGE2, rIFN-gamma, rIL-Ialpha, rIL-1beta, rIL-6, or rIL-12. Production of IgG1, IgG2, IFN-gamma, and PGE2 was monitored by enzyme-linked immunosorbent assay.

RESULTS

Indomethacin treatment inhibited IgG1 and IgG2 production, and PGE2 restored both immunoglobulins in PWM-stimulated cultures. Remarkably, addition of IFN-gamma also restored IND-suppressed IgG2 but not IgG1. In contrast, addition of rIL (interleukin)-1alpha, rIL-1beta, rIL-6, or rIL-12 did not restore IgG2 responses. Furthermore, IND suppressed IFN-gamma production and PGE2 increased IFN-gamma levels. Kinetic studies indicate that PGE2 production occurred on the first day of culture, followed by IFN-gamma two days later.

CONCLUSIONS

These findings support the concept that in certain circumstances, PGE2 production can lead to increased IFN-gamma and that this IFN-gamma selectively promotes IgG2 responses. These data suggest that the elevated PGE2 observed in LAgP patients may contribute to increased IFN-gamma production and help explain elevated IgG2 responses.