| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2001: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
It has been known that, in mammals, various microbial or viral components, represented by lipopolysaccharide (LPS), activate innate immune cells via Toll-like receptor (TLR). However, cellular responses against fungi, another types of important pathogens, remain to be analyzed. In this study, we analyzed macrophage activating activities of β-glucans on the surface of fungi to reveal molecular mechanisms for the recognition of pathogens via TLRs and cellular activation.
When the activities of various β-glucans to stimulate MF-κβ, a linear (1→3) - β-_D-glucan preparation, curdlan, exhibited the strongest activity. The activity cordlan, which is insoluble at neutral pH, was markedly enhanced by dissolving it in 50-300 mM NaOH. Curdlan activated NF-κB and induced the expression of tumor necrosis factor-α, macrophage inflammatory protein-2, and inducible nitric-oxide synthase. The activity of curdlan was not inhibited by polymyxin B, which neutralizes the activity of LPS. In contrast, the activity of curdlan was dose-dependently inhibited by β-glucan-binding domain of horseshoe crab factor G or short (1→3)-β-_D-glucans. Furthermore, the cellular response to curdlan was inhibited by overexpression of a mutant MyD88, an adaptor molecule essential for TLR/IL-1 receptor signaling pathways. These results indicate that linear (1→3)-β-_D-glucans stimulate macrophage depending on their tertiary structures and strongly suggest that the receptor for the glucans is a Toll/IL-1 receptor-like (TIR) domain-containing membrane protein(s), such as TLRs.
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