Structure-activity relationship of (1-->3)-beta-D-glucans in the induction of cytokine production from macrophages, in vitro

Okazaki M, Adachi Y, Ohno N, Yadomae T

Laboratory of Immunopharmacology of Microbial Products School of Pharmacy, Tokyo
University of Pharmacy and Life Science, Japan.

In a previous study, we reported that one of the gel-forming (1-->3)-beta-D-glucans, grifolan
(from Grifola frondosa, GRN), stimulated cytokine production from macrophages in vitro.
However, several other gel-forming (1-->3)-beta-D-glucans, such as sonifilan (SPG) and SSG,
did not induce cytokine production from macrophages. The ultrastructure of gel-forming
(1-->3)-beta-D-glucans, especially the triple- and single-helix, does not affect the
cytokine-inducing activity. The action on tumor necrosis factor alpha (TNF alpha) release was
correlated with the molecular weight of GRN, since the highest molecular weight fraction of
GRN, Mr > or = 45000, exhibited the strongest activity. Although, native SSG (Mr > or =
2000000) did not induce cytokine production, chemical modification involving debranching of the
side chain glucosyl residues of SSG resulted in TNF alpha inducing activity. These results suggest
that the branching ratio and molecular weight of (1-->3)-beta-D-glucans are important factors for
the production of cytokines from macrophages. GRN-inducible TNF alpha release was reduced
by co-culturing with SPG, SSG, or the soluble beta-glucan, laminarin (LAM). Pretreatment alone
with SPG or LAM was not sufficient for significant inhibition of GRN-inducible TNF alpha
release. TNF alpha production induced with 50 micrograms/ml of zymosan (ZyM) was also
reduced by addition of SPG, but TNF alpha production, stimulated with a higher concentration
(100 micrograms/ml) of ZyM or with lipopolysaccharide (LPS), was not reduced significantly.
The inhibitory effect of LAM on the uptake of GRN by RAW264.7 cells was not completely
correlated with TNF alpha release. These results suggest that macrophages may incorporate
beta-glucans through certain (1-->3)-beta-D-glucan-specific mechanisms and/or other
endocytosis pathways, and that the beta-glucan-specific route is partially associated with
cytokine production. In conclusion, TNF alpha release by macrophages is induced only by
beta-glucans with high molecular weights and lower branching ratios, and the mechanism for the
recognition of beta-glucans is multiple and assumed to be divided into several parts involving
various cellular functions.

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