Regulation of B-lymphocyte proliferative responses by arachidonate metabolites: effects on membrane-directed versus intracellular activators.

Immunoregulatory effects of the oxidative metabolites of arachidonic acid (AA) on proliferation of B-lymphocytes were assessed in a serum-free culture system. Activation of B cells by membrane-directed ligands and intracellular activators was regulated by AA metabolites in very distinct fashions. Thus exogenous cyclooxygenase products (particularly prostaglandins E1 and E2) amplified the response to anti-immunoglobulin antibodies, whereas lipoxygenase products damped this response. In contrast, B cell activation with 8-mercaptoguanosine (an intracellular activator) was inhibited by cyclooxygenase products and remained relatively unaffected by several lipoxygenase products tested. This pattern of results was confirmed in studies with pathway inhibitors. Moreover, when liberation of endogenous AA was induced by stimulation of phospholipase A2 activity with melittin, inhibition of the response to each class of activator was counteracted with the appropriate pathway inhibitor. Results suggest that the two major groups of AA oxidation products function as a system of counterbalancing regulatory influences, serving to modulate B cell activation at the plasma membrane and to downregulate B cell activation at the intracellular level.