title: Toll-like receptor 2 and Toll-like receptor 4-dependent activation of B cells by a polysaccharide from marine fungus Phoma herbarum YS4108.
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 immunomodulating 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.
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, PR China.
authors.forename: Xian
authors.initials: X
authors.lastname: Zhang
authors.forename: Ran
authors.initials: R
authors.lastname: Ding
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Rui
authors.initials: R
authors.lastname: Zhu
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Lei
authors.initials: L
authors.lastname: Jin
authors.forename: Wenbing
authors.initials: W
authors.lastname: Yao
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Gao
mesh_terms: D000818:Animals; D001203:Ascomycota / Q000276:immunology*; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D002478:Cells, Cultured; D062610:Fungal Polysaccharides / Q000276:immunology*; D007075:Immunoglobulin M / Q000276:immunology; D007155:Immunologic Factors / Q000276:immunology*; D020935:MAP Kinase Signaling System; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology*
chemical_list: D062610:Fungal Polysaccharides; D007075:Immunoglobulin M; D007155:Immunologic Factors; D016328:NF-kappa B; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4
references.citation: Acc Chem Res. 2006 May;39(5):354-61
references.pmid: 16700534
references.citation: Cell. 2010 Mar 19;140(6):805-20
references.pmid: 20303872
references.citation: Nature. 2009 Apr 30;458(7242):1191-5
references.pmid: 19252480
references.citation: Cell. 2004 May 28;117(5):677-87
references.pmid: 15163414
references.citation: PLoS One. 2008;3(10):e3509
references.pmid: 18946502
references.citation: J Biol Chem. 1999 Jun 18;274(25):17406-9
references.pmid: 10364168
references.citation: J Immunol. 2002 Dec 1;169(11):6149-53
references.pmid: 12444118
references.citation: J Biol Chem. 2006 Aug 25;281(34):24111-23
references.pmid: 16798741
references.citation: Int Immunopharmacol. 2008 Dec 20;8(13-14):1835-41
references.pmid: 18834960
references.citation: Nat Rev Immunol. 2004 Jul;4(7):499-511
references.pmid: 15229469
references.citation: Nat Prod Rep. 2011 Feb;28(2):290-344
references.pmid: 21229157
references.citation: J Immunol. 1999 Apr 1;162(7):3749-52
references.pmid: 10201887
references.citation: Biochimie. 2010 Apr;92(4):411-7
references.pmid: 20004229
references.citation: Carbohydr Res. 2012 Jul 15;356:260-4
references.pmid: 22507831
references.citation: Cytokine. 2010 Jan;49(1):1-9
references.pmid: 19775907
references.citation: Cell. 2007 Sep 21;130(6):1071-82
references.pmid: 17889651
references.citation: Planta Med. 2012 Jan;78(1):76-8
references.pmid: 21969116
references.citation: J Leukoc Biol. 2007 Nov;82(5):1027-32
references.pmid: 17615380
references.citation: J Immunol. 2007 Jun 15;178(12):7779-86
references.pmid: 17548615
references.citation: Int Immunopharmacol. 2003 Sep;3(9):1301-12
references.pmid: 12890428
references.citation: Vaccine. 1996 Feb;14(3):190-8
references.pmid: 8920699
references.citation: J Biol Chem. 2011 May 20;286(20):17736-45
references.pmid: 21454596
references.citation: Planta Med. 2002 Apr;68(4):363-5
references.pmid: 11988865
references.citation: J Immunol. 2005 Jun 1;174(11):7043-9
references.pmid: 15905547
references.citation: Microb Biotechnol. 2010 Sep;3(5):544-63
references.pmid: 21255352
references.citation: Nucleic Acids Res. 1991 May 11;19(9):2499
references.pmid: 2041787
references.citation: Trends Microbiol. 2004 Jan;12(1):44-9
references.pmid: 14700551
references.citation: Clin Immunol. 2006 Sep;120(3):272-84
references.pmid: 16766226
references.citation: J Immunol. 2012 Aug 1;189(3):1440-7
references.pmid: 22730531
references.citation: N Engl J Med. 2012 Jun 7;366(23):2207-14
references.pmid: 22646510
references.citation: Int Immunopharmacol. 2006 Dec 5;6(12):1815-24
references.pmid: 17052672
references.citation: Curr Opin Immunol. 2005 Jun;17(3):230-6
references.pmid: 15886111
references.citation: Glycobiology. 2012 Jan;22(1):146-59
references.pmid: 21873606
references.citation: Immunology. 2009 Nov;128(3):311-23
references.pmid: 20067531
references.citation: Biochimie. 2005 Aug;87(8):747-54
references.pmid: 15885873
references.citation: Nature. 2005 Nov 17;438(7066):364-8
references.pmid: 16292312
references.citation: Immunol Rev. 2000 Aug;176:154-70
references.pmid: 11043775
references.citation: Acta Pharmacol Sin. 2009 Jul;30(7):1008-14
references.pmid: 19575004
references.citation: Immunity. 2001 May;14(5):617-29
references.pmid: 11371363
references.citation: Nat Commun. 2012 Apr 03;3:767
references.pmid: 22473011
references.citation: Carbohydr Res. 2003 Nov 14;338(23):2539-47
references.pmid: 14670715
references.citation: J Ethnopharmacol. 2011 Apr 26;135(1):1-6
references.pmid: 20600759
references.citation: J Nat Prod. 2003 Apr;66(4):511-4
references.pmid: 12713403