Upon PS F2 stimula tion, BMDMs from C3H/HeJ mice produced a signifi cantly lower level of TNF compared with the BMDMs from wild type C3H/HeN selleck kinase inhibitor mice. In contrast, the BMDMs from these two mouse strains showed similar responses to poly stimula tion, indicating that PS F2 specifically stimulates macro phages via TLR4. Consistent with the results in Figure 1D, addition of laminarin could suppress PS F2 stimulated TNF production in both wild type and TLR4 mutant BMDMs, and the stimulatory effect was almost completely eliminated in TLR4 mutant BMDMs when laminarin was present. Although TLR2 has been reported to recognize fungal polysaccharides, it is not responsible for recognizing PS F2 since BMDMs derived from wild type and TLR2 mice from G.
lucidum interacted with a number of innate immune receptors, including Dectin 1, DC SIGN, Langerin, Kupffer cell receptor, macrophage mannose receptor, TLR2 and TLR4. Based on our and others findings, it is clear that the innate immune cells can utilize multiple PRRs for recognition of the heteropoly saccharides in fungal cell walls. Different cell types may have different expression patterns of various PRRs, which would determine the outcome of polysaccharide stimulation. We have routinely observed that PS F2 stimulated a significantly higher level of TNF pro duction in RAW264. 7 cells than in BMDMs. Besides the difference in cell origins, we speculate that the relative expression levels of various PRRs may be different between these two types of macrophages, resulting in the difference in response to PS F2 stimulation.
Prior exposure of innate immune cells to LPS causes them to become refractory to subsequent LPS challenge, a phenomenon called LPS tolerance. To test the possibility that prior LPS or PS F2 exposure would make macrophages refractory to subsequent PS F2 stimulation, RAW264. 7 cells were stimulated with LPS or PS F2, then subjected to secondary stimulation with LPS or PS F2 5 hours later. As expected, LPS exposed macrophages did not show further TNF production after second LPS challenge. However, if cells responded equally well to PS F2 stimulation. Collectively, our data demonstrate that Dectin 1, CR3 and TLR4 are the three major receptors involved in the detection of PS F2 by macrophages. Although the carbohydrate structure in PS F2 that is recognized by TLR4 remains to be determined, it appears that TLR4 can detect carbohydrate containing PAMPs.
Several studies also report that polysaccharides from various fungal species, including G. lucidum, stimulate immune cell activation via TLR4. In addition, TLR4 also Cilengitide serves as a receptor for botanical polysaccharides which exhibit immunostimulatory activ ities. Using a carbohydrate receptor binding assay, a recent study showed that the polysaccharides extracted were pretreated with LPS or PS F2, subsequent PS F2 stimulation could further increase the production of TNF.
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