Intracellular Signaling Events Associated with the Induction of DNA Synthesis in Human B Lymphocytes: II. Different Pathways Triggered by IL-2 and IL-4

In attempts to detect associations between early signaling events triggered by interleukins and the induction of DNA synthesis, inhibitors of various second messenger pathways were tested for their effects on IL-2- and IL-4-elicited mitogenesis in preactivated human B lymphocytes. Inhibitors of phosphoinositidase C and of InsP3-induced calcium release suppressed IL-4- but not IL-2-mediated proliferation. The response to both lymphokines was also impaired by an inhibitor of the calcium/calmodulin complex and was modulated by variations of the [Ca2+]i. PKC inhibitors and PK-C depletion did not significantly alter the response to IL-2 and IL-4. The response to IL-2, but not to IL-4, was inhibited by cAMP analogues or by agents that raise cAMP. In contrast, IL-4, but not IL-2, stimulated cAMP accumulation in activated B cells. Taken together, these observations indicate that IL-2 and IL-4 use different signaling pathways to induce the G1 → S transition in these cells and suggest that the IL-4 inhibition of the B cell response to IL-2 may result from its effect on cAMP generation.