Toll-Like Receptor 2 and Toll-Like Receptor 4-Dependent Activation of B Cells by a Polysaccharide from Marine Fungus Phoma herbarum YS4108

Xian Zhang,Ran Ding,Yan Zhou,Lei Jin,Rui Zhu,Xiangdong Gao,Wenbing Yao,Wei Liu,Robert Lafrenie

doi:10.1371/journal.pone.0060781

Xian Zhang, Ran Ding + Show 7 more

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https://doi.org/10.1371/journal.pone.0060781

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Journal: PloS one	Publication Date: Mar 29, 2013
Citations: 59	License type: CC BY 4.0

Affiliation: China Pharmaceutical University

Abstract

Various natural polysaccharides are capable of activating the immune system and therefore can be employed as biological response modifiers in anti-tumor therapy. We previously found a homogenous polysaccharide from the mycelium of marine fungus Phoma herbarum YS4108, named YCP, exhibiting strong in vivo antitumor ability via enhancement of the host immune responses. To further elucidate the role of YCP as a biological response modifier, the immunomoduating activities of YCP in B cells was investigated in the current study. We demonstrated that stimulation of YCP with murine splenic B cells resulted in cell proliferation and generation of IgM antibody response. Binding of YCP to B cells was a direct, saturable and reversible event and required TLR2 and TLR4 involvement. TLR2 and TLR4 defunctionalization by either antibody blocking or allele-specific mutation significantly impaired the B-cell proliferative and IgM responses to YCP. YCP interaction with TLR2 and TLR4 led to the activation of intracellular p38, ERK and JNK, as well as the translocation of transcriptional factor NF-κB into nucleus. Furthermore, specific inhibitors of p38, ERK, JNK and NF-κB could attenuate the ability of YCP to induce B cell proliferation and IgM production. Taken together, this study has indicated for the first time the immunostimulating properties of YCP on B cells through a receptor-mediated mechanism, which involves TLR2 and TLR4 and resultant activation of MAPK and NF-κB signaling pathways, thereby highlighting the role of YCP as an efficacious biological response modifier in oncologic immunotherapy.

Highlights

In recent decades, marine-derived fungi have garnered much attention as a rich source of novel bioactive compounds due to their strong adaptability to cold, lightless and high-pressure environments in oceanic realm [1,2]
We find that YCP is capable of inducing proliferation and antibody production in B cells, the mechanism of which is direct, saturable and reversible binding of YCP to TLR2 and TLR4 with subsequent activation of mitogen-activated protein kinases (MAPKs) and nuclear factor -kB (NF-kB) signaling pathways
The results indicated that YCP significantly stimulated B cell to proliferate in a dosedependent manner (Figure 1A)

Summary

Introduction

Marine-derived fungi have garnered much attention as a rich source of novel bioactive compounds due to their strong adaptability to cold, lightless and high-pressure environments in oceanic realm [1,2]. A novel homogenous polysaccharide referred to as YCP (YCP is the acronym of Yancheng polysaccharide) was purified from the mycelium of Phoma herbarum YS4108 that inhabits the sediment in the Yellow Sea area around Yancheng, China. It has a backbone of a-1,4-D-glucan with a lower proportion of a-1,6-linked glucopyranosyl and glucuronic acid residues as non-reducing terminals [8]. Given that the strategy of oncologic immunotherapy through biological response modifiers (BRMs) has been figured out to function in clinic [12], it can be expected that the polysaccharide YCP holds much promise as a novel antitumor drug with high effectiveness and low toxicity

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