Influence of ganglioside GM₃ and its breakdown products on lymphoblastic transformation and T‐suppressor activity

Abstract

The influence of ganglioside GM3 and some of its breakdown products on phytohemagglutinin‐induced blast transformation of human lymphocytes and concanavalin‐A‐induced T‐suppressor activity was studied. The structures of two major hydrolysis products of GM3 were established by negative‐ion fast‐atom‐bombardment mass spectrometry as neuraminyllactosylsphingosine (NeuLacSph) and neuraminyllactosylceramide (NeuLacCer). Both substances were shown to be potent inhibitors of mitogen‐induced lymphoblastic transformation whereas their acetylation products NeuAcLacSphAc and GM3 did not affect the proliferative response of lymphocytes to phytohemagglutinin. On the other hand, only GM3 and NeuLacSph were able to enhance concanavalin‐A‐induced T‐suppressor activity. On the basis of these data, it is suggested that the effects of GM3 and its breakdown products on lymphoblastic transformation and T‐suppressor activity must rest on different mechanisms and that N‐deacylation of GM3 appears to be an essential step in conversion of the ganglioside into an inhibitor of lymphocyte blast transformation.

Ganglioside GM3 Inhibits lnterleukin-3-Dependent Bone Marrow-Derived Mast Cell Proliferation

“…Ganglioside GM3 inhibited growth stimulation by fibro blast growth factor [1], regulated receptor function of epi dermal growth factor [2] and integrin receptor function [3,4], Concerning the effect of the modulation of immune function, ganglioside GM3 showed an inhibitory effect on natural killer cytotoxicity and an enhancement of T sup pressor cell activity [5,6], Moreover, suppresion of interleu kin-2 (IL-2) activity and inhibition of IL-2-and interleu kin-4 (IL-4)-dependent T cell proliferation were observed by the addition of exogenous GM3 [7][8][9]. Thus, these things suggested that GM3 may play a role in the regulation of T lymphocyte functions.…”

Gangliosides and antitumor immunity

“…However, evidence on the dependence of the suppressive effect on the ganglioside structure is still incomplete and frequently contradictory. This led us to undertake a systematic study of the influence of various gangliosides on the response of lymphocytes to the action of the plant-derived mitogen phytohemagglutinin [12][13][14].…”

“…The disialogangliosides GD3 and GDla and the glucosamine-containing ganglioside IV3NeuAc-nLc4Cer displayed a strong inhibitory effect whereas the monosialogangliosides GMI and GM3 had only very weak if any influence on the induction of lymphocytic blast transformation by the mitogen (Cer = ceramide; Neu = neuraminic acid; Sph = sphingosine). At the same time, however, some breakdown products of GM3 (its de-Nacetyl and de-N-acetyl-de-N-acyl derivatives NeuLacCer and NeuLacSph) significantly inhibited Glycosphingolipid concentration = 50 nmol/ml phytohemagglutinin-stimulated thymidine incorporation at very low concentrations [14]. This effect was not due to cytotoxic or cytostatic action of the gangliosides, and their direct interaction with phytohemagglutinin seemed to be excluded as inhibitory mechanism because significant inhibition was seen already at ganglioside :mitogen molar ratios of 1:15 or less [12,13].…”

“…Accordingly, we incubated human peripheral blood lymphocytes as described by Shou et al but either in the presence or in the absence of individual, well-defined gangliosides [10,[12][13][14]. T-suppressor activity was then determined by measuring [3H]thymidine incorporation upon incubation with allogeneic lymphocytes and phytohemagglutinin.…”

“…To obtain additional information on that subject we studied the influence of exogeneous individual gangliosides on the phytohemagglutinin-induced lymphoblastic transformation and the T-suppressor activity of human peripheral blood lymphocytes as well as on the cytotoxic action of natural killer (NK) cells [3,10,[12][13][14].…”