Regulation of human B cell activation by prostaglandin E₂. Suppression of the generation of immunoglobulin-secreting cells

The role of prostaglandin E₂ (PGE₂) in the generation of immunoglobulin-secreting cells (ISC) from human peripheral blood B cells was examined. Initial studies demonstrated that monocyte (MΦ)-mediated suppression of the generation of ISC in Staphylococcus aureus (SA)-stimulated cultures was mitigated by indomethacin, and thus suggested that the cyclooxygenase pathway products of arachidonic acid played a role in the regulation of B cell activation. The possibility that PGE₂, one of the major products of this pathway generated by MΦ-affected human B cell responses, was therefore investigated. PGE₂ was found to cause concentration-dependent inhibition of the generation of ISC in pokeweed mitogen- or SA-stimulated B cell cultures supported by T cells. Studies were therefore carried out to determine whether PGE₂ inhibited the production of necessary T cell factors or directly altered B cell responsiveness. Initially, the effect of PGE₂ on the capacity of mitogen-stimulated cells to secrete a factor that supported the differentiation of B cells into ISC was investigated. Excessive numbers of MΦ or PGE₂ inhibited the production of B cell differentiation factor from mitogen-stimulated T cells. The effect of PGE₂ on the capacity of B cells to differentiate into ISC was more complex. PGE₂ inhibited the generation of ISC when B cells were stimulated with SA and B cell differentiation factor-containing T cell supernatants. PGE₂-mediated inhibition of ISC generation was observed even when addition of PGE₂ was delayed until after ISC first were detected in culture. By contrast, PGE₂ caused only minimal inhibition of the generation of ISC cultures stimulated by T cell supernatants alone or protein A-free SA and T cell supernatants. These results suggested that SA-responsive B cells were particularly sensitive to inhibition by PGE₂. Additional experiments supported the conclusion that B cell sensitivity to inhibition by PGE₂ is augmented by the immunoglobulin cross-linking effects of protein A-containing SA. Overall, the results support the conclusion that PGE₂ at physiologically relevant concentrations can influence human antibody responses by means of a direct inhibitory action on the responding B cell or an indirect one on the production of necessary T cell factors.