LIGATION OF CD23 TRIGGERS CYCLIC-AMP GENERATION IN HUMAN B-LYMPHOCYTES

The low affinity IgE receptor CD23 may play a role in several B lympho cyte functions, such as cell activation and multiplication, Ag present ation, and IgE production. We have previously reported that ligation o f the CD23 molecule with anti-CD23 mAb, or IgE-anti-IgE complexes, lea ds to phosphoinositide hydrolysis and calcium mobilization through the generation of Inositol (1,4,5) trisphosphate via a process involving a Pertussis toxin insensitive GTP-binding protein. In our work, we sho w that anti-CD23 mAb elicit an increase in cAMP concentration in human peripheral blood-derived B lymphocytes. This effect was detected both in resting and in IL-4-stimulated B cells displaying, respectively, l ow and high levels of CD23. Maximum cAMP accumulation was reached abou t 20 min after addition of the mAb. Involvement of FcgammaRII in this process could be excluded because cAMP increase was also triggered by mAb anti-CD23 F(ab')2 fragments. Accumulation of cAMP was also observe d when IgE-sensitized activated B lymphocytes were challenged with the specific hapten. Several lines of evidence indicate that the cAMP inc rease after CD23 ligation may result, in part, from the stimulation of phosphoinositidase C, inasmuch as it was markedly impaired by treatme nt with TMB-8, an inhibitor of InsP3-induced calcium release from intr acytoplasmic stores and with BAPTA, an intracellular calcium chelator. Addition of GTP-gammaS to permeabilized B cells or to membrane prepar ations did not potentiate the effect of the mAb, suggesting that a Gs protein is not directly implicated in the generation of cAMP. Besides, cAMP accumulation is not due to the production of PG because it is no t modified by indomethacin, an inhibitor of the cyclooxygenase pathway . Pretreatment of B lymphocytes with either anti-CD23 mAb or IL-4 led to autologous as well as heterologous desensitization. This negative c ross-talk, at the level of cAMP, between the signaling pathways trigge red by ligation of CD23 and of the IL-4 receptor, could contribute to the inhibitory effect of anti-CD23 mAb on IL-4-dependent B cell activa tion and differentiation.