Soluble β-glucan from Grifola frondosa induces proliferation and Dectin-1/Syk signaling in resident macrophages via the GM-CSF autocrine pathway.
MD-Fraction, a highly purified, soluble β-(1,3) (1,6)-glucan obtained from Grifola frondosa (an oriental edible mushroom), has been reported to inhibit tumor growth by modulating host immunity. β-Glucan, a major component of the fungal cell wall, is generally recognized by PRRs expressed on macrophages and DCs, such as Dectin-1, and the ability of β-glucans to modulate host immunity is influenced by their structure and purity. Most cellular studies have used particulate β-glucans, such as yeast zymosan (crude β-glucan) and curdlan (purified β-glucan). However, little is known about the cellular mechanism of soluble β-glucans, including MD-Fraction, despite significant therapeutic implications. In this study, we investigated the cellular mechanism of MD-Fraction in murine resident macrophages and compared it with two well-known β-glucan particles. MD-Fraction induced GM-CSF production rapidly through Dectin-1-independent ERK and p38 MAPK activation. Subsequently, MD-Fraction-induced GM-CSF enhanced proliferation and Dectin-1 expression, which permitted Dectin-1-mediated TNF-α induction through the Syk pathway. Curdlan induced not only the proliferation and activation of Dectin-1/Syk signaling in a manner similar to MD-Fraction but also the uncontrolled, proinflammatory cytokine response. Contrastingly, zymosan reduced proliferation and Dectin-1 expression significantly, indicating that the mechanism of macrophage activation by MD-Fraction differs from that of zymosan. This is the first study to demonstrate that purified β-glucans, such as MD-Fraction and curdlan, induce GM-CSF production directly, resulting in Dectin-1/Syk activation in resident macrophages. In conclusion, we demonstrated that MD-Fraction induces cell proliferation and cytokine production without excessive inflammation in resident macrophages, supporting its immunotherapeutic potential.
Department of Microbial Chemistry, Kobe Pharmaceutical University, Kobe, Japan. organic@kobepharma-u.ac.jp
Yuki
Y
Masuda
Takuya
T
Togo
Shigeto
S
Mizuno
Morichika
M
Konishi
Hiroaki
H
Nanba
D000363:Agaricales / Q000737:chemistry* / Q000276:immunology; D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects* / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002473:Cell Wall / Q000737:chemistry / Q000276:immunology; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology* / Q000378:metabolism; D037181:Lectins, C-Type / Q000096:biosynthesis / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D011505:Protein-Tyrosine Kinases / Q000276:immunology* / Q000378:metabolism; D000072377:Syk Kinase; D047071:beta-Glucans / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism; D000099181:Dectin-1
D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; D047071:beta-Glucans; D048051:p38 Mitogen-Activated Protein Kinases; D000099181:Dectin-1; C000606897:Syk protein, mouse