The skewing to Th1 induced by lentinan is directed through the distinctive cytokine production by macrophages with elevated intracellular glutathione content

Abstract

In vivo lentinan (LNT)-elicited peritoneal macrophages (Mps) showed the reduced release of prostaglandins (PGs), IL-10 and IL-6, while it endowed Mps with the elevated capability to produce IL-12 and nitric oxide (NO) upon in vitro triggering, due to the elevated intracellular glutathione (GSH) content in Mps. Deprivation of intracellular GSH completely ablated the production of IL-12. Conversely, lipopolysaccharide (LPS) induced peritoneal Mps with the reduced intracellular GSH content and the reciprocal profile of mediator production. Mps with the elevated intracelluar GSH is arbitrarily termed as reductive Mp (RMp) and that with reduced amount as oxidative Mp (OMp). OMp was converted to RMp when GSH was replenished with glutathione monoethylester (GSH-OEt). The IL-2 administration in combination with LNT exerted the synergistic induction of RMp, resulting in synergistic augmentation of IL-12, NO and reduction of IL-6 production. It was also confirmed that CD4+T cells derived of LNT-administered mice showed augmented IFN-gamma and reduced IL-4 production upon in vitro anti-CD3 stimulation. Taken together it is concluded that skewing of Th1/Th2 balance to Th1 by a beta-(1-3)-glucan, LNT, is directed through the distinctive production of IL-12 versus IL-6, IL-10 and prostaglandin E2 (PGE2) by Mps, depending on intracellular GSH redox status. To the efficient tumor immunotherapy, it may be one of the critical elements to induce a reductive form of Mps in tumor stromal tissues to maintain Th1 response.