title: IL-4 acts as a homeostatic regulator of IL-2-induced TNF and IFN-gamma.
abstract: 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-gamma), 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-gamma. 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-gamma secretion in both groups. The addition of recombinant IL-4 to these IL-2-stimulated cultures lead to significant inhibition of IFN-gamma and TNF production. IFN-gamma secretion was reduced by 50-99% in normal donors and by between 11% and 99% in patients (P less than 0.001). TNF levels induced by IL-2 were similarly reduced by IL-4 both in normal donors (P less than 0.003) and in patients (P less than 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-gamma and TNF were secreted (P less than 0.05). Since both TNF and IFN-gamma 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.
authors.affiliation: Department of Haematology, Royal Free Hospital, London, U.K.
authors.forename: C
authors.initials: C
authors.lastname: Bello-Fernandez
authors.forename: P
authors.initials: P
authors.lastname: Oblakowski
authors.forename: A
authors.initials: A
authors.lastname: Meager
authors.forename: A S
authors.initials: AS
authors.lastname: Duncombe
authors.forename: D M
authors.initials: DM
authors.lastname: Rill
authors.forename: A V
authors.initials: AV
authors.lastname: Hoffbrand
authors.forename: M K
authors.initials: MK
authors.lastname: Brenner
mesh_terms: D016026:Bone Marrow Transplantation / Q000276:immunology; D002478:Cells, Cultured; D006706:Homeostasis / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D007376:Interleukin-2 / Q000276:immunology*; D015847:Interleukin-4 / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology; D009369:Neoplasms / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007371:Interferon-gamma