Biphasic effect of cyclic AMP on an immune response

Abstract

AGENTS which enhance intracellular adenosine 3′, 5′—monophosphate (cyclic AMP) levels by inhibiting cyclic AMP phosphodiesterase activity can increase the number of antibody forming cells (AFC) in humoral immunity both in vivo^1,2 and in vitro^3,4. Thus, cyclic AMP is a potential mediator of immune induction. But the same agents, at higher than optimal levels, can inhibit the AFC response^1,3. Experiments have been done suggesting⁵ that enhanced intracellular cyclic AMP is a mediator of immune paralysis, or tolerance. The apparently contradictory conclusions drawn from these various experiments may be resolved if one considers a common kinetic feature of cyclic AMP responses to various agents, in lymphoid^6–8 and in non-lymphoid^9,10 cells; namely, that the rise in cyclic AMP level is transitory, and the cyclic nucleotide level returns to control values after a few minutes or hours. A similar transient rise in cyclic GMP lias been noted in phytohaemagglutinin-stimulated peripheral leukocytes, where this nucleotide seems to mediate the blastogenic response to the mitogen¹¹. Thus, the same agents which might enhance an AFC response if present during the increased cyclic AMP phase, could inhibit the response if present during the subsequent phase of declining intracellular cyclic AMP. To see if this pattern was in fact part of an immune response in vitro, we performed experiments with sheep erythrocytes as immunising antigen, and varied the time of exposure of the immunocompetent cells to the agents N⁶, 2′-O-dibutyryl cyclic AMP or aminophylline. When present only during the first 12 or 24 h of exposure to antigen, these agents increased the number of AFC seen after 4 or 5 d of culture. But they inhibited the response if present during days 2 or 3. The effects of increasing intracellular cyclic AMP during the early period were twofold: (1) there was a delay in the arrival of cells at the antibody-secreting stage, and (2) the number of AFC at the optimal time was increased.