CROSS-TALK BETWEEN B-CELL SURFACE-IMMUNOGLOBULIN AND INTERLEUKIN-4 RECEPTORS - THE ROLE OF PROTEIN-KINASE-C AND CA-2+-MEDIATED SIGNALS

A well‐known property of IL 4 is its capacity to synergize with low concentrations of anti‐immunoglobulin (Ig) antibodies to induce B cells to synthesize DNA. Cross‐linking of surface Ig receptors stimulates phosphoinositide hydrolysis, with consequent production of two signals: the elevation of intracellular Ca2+ levels and activation of protein kinase C (PKC). Little is known about the second messengers utilized by interleukin (IL)4 receptors. In this study we have investigated the relative contributions of the two signals emanating from the ligation of surface Ig receptors to the synergistic activation of B cells by IL 4. We show that IL 4 plus carefully titrated concentrations of PKC‐activating phorbol esters [such as phorbol 12,13‐dibutyrate (PBu2)] induce cell cycle entry of virtually all murine B cells and substantial levels of DNA synthesis. Ca2+ ionophores, in contrast do not act as co‐mitogens with IL 4. However, a critical concentration of ionomycin further enhanced DNA synthesis induced by PBu2 plus IL 4. Taken together, these results suggest that PKC activation alone is sufficient to synergize with IL 4 in inducing B cells to enter cell cycle. However, the co‐mitogenic effects of anti‐Ig and IL 4 are evidently also dependent on Ca2+ signals. This interpretation is supported by the findings that cyclosporin, which abrogates the activation of lymphocytes by Ca2+‐dependent stimuli, inhibits B cell proliferation induced by anti‐Ig plus IL 4, but not the response to PBu2 plus IL 4. Copyright © 1990 Wiley‐VCH Verlag GmbH & Co. KGaA