IL-4 acts as a homeostatic regulator of IL-2-induced TNF and IFN-γ

Interleukin-4 (IL-4) is a cytokine secreted by interleukin-2 (IL-2)-activated lymphocytes. IL-2-stimulated lymphocytes also secrete two cytokines, tumour necrosis factor (TNF) and gamma-interferon (IFN-γ), which contribute to effector function and which may themselves recruit fresh, cytokine-secreting effector cells. We have now investigated whether the IL-4 induced is able to homeostatically regulate secretion of the TNF and IFN-γ. Peripheral blood mononuclear cells or lymphocytes from normal donors and from patients with neoplastic disease were cultured in the presence of IL-2 alone, IL-4 alone or with both cytokines. IL-2 induced high levels of TNF and IFN-γ secretion in both groups. The addition of recombinant IL-4 to these IL-2-stimulated cultures leads to significant inhibition of IFN-γ and TNF production. IFN-γ secretion was reduced by 50-99% in normal donors and by between 11% and 99% in patients (P < 0.001). TNF levels induced by IL-2 were similarly reduced by IL-4 both in normal donors (P < 0.003) and in patients (P < 0.01). These inhibitory effects were produced by IL-4 at doses of IL-2 attainable in vivo. Inhibition appears to represent a homeostatic regulatory mechanism which may limit recruitment of fresh activated killer (AK) cells. When endogenous IL-4 activity in IL-2-activated lymphocytes was blocked by anti-IL-4 antibody, significantly higher levels of IFN-γ and TNF were secreted (P < 0.05). Since both TNF and IFN-γ may contribute to the anti-neoplastic action of IL-2, manipulating the level of IL-4 activity in vivo could augment the benefits of IL-2 immunotherapy.