Immunomodulatory Effects of Natural Products on TLR Expression and Signal Transduction

Toll-like receptors (TLRs) are an essential component for bacterial recognition and initiation of signaling pathways necessary for induction of cytokines, chemokines and co-stimulatory molecule expression in immune cells. Interestingly, there are several reports of inhibition of TLR induction by various medicinal plant-derived products such as ginsan in response to bacterial infection. Expression of TLRs, including TLR2, TLR4 and TLR9, as well as the adaptor molecule MyD88 was considerably reduced in peritoneal macrophages treated with ginsan before a subsequent contact with S. aureus (Ahn et al., 2006). It is believed that host pattern recognition proteins belonging to the TLR family are involved in protective innate immune responses against Lp infection. In particular, TLR2 appears to play a defined role in host resistance, at least in the murine model, though other TLRs are likely involved. In the murine host in which macrophages are permissive for Lp infection, the intracellular growth of the pathogen is enhanced within TLR2/- macrophages compared to WT mice and TLR4/- macrophages (Akamine et al., 2005). In vivo growth of Lp is also enhanced in the lungs of TLR2 deficient mice, which results in delayed bacterial clearance (Archer and Roy, 2006).

Recent reports also demonstrate that the plant-derived tea catechin EGCG inhibits TLR2 induction by BMDCs caused by bacterial infection or treatment with bacterial products. In particular, EGCG inhibited both Lp and LPS induction a. DC only t»DW

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Figure 10.3. EGCG inhibits induced TLR2 on DCs infected with a) L. pneumophila (Lp) or b) stimulated with LPS and treated with various concentrations of EGCG analyzed by flow cytometry. Numbers in quadrants reflect percentages rounded to next greater whole integer. Results shown are 1 of 3 independent experiments with similar results.

of TLR2 (Fig. 10.3). TLR2 is considered a signal transducer for Lp since either viable or killed Lp activate DCs in TLR4-deficient mice, but not in TLR2 knockout A/J mice. A similar inhibition of TLR4 induction was also demonstrated in response to Lp infection (Fig. 10.4).

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Figure 10.4. EGCG inhibits induced TLR4 on DCs infected with L. pneumophila (Lp) and treated with various concentrations of EGCg analyzed by flow cytometry. Numbers in quadrants reflect percentages rounded up to next greater whole integer. Results shown are 1 of 3 experiments with similar results.

A common theme among many plant-derived products having medicinal properties is inhibition of relB, a subunit of the NFkB pathway. The promoter region of the TLR2 gene contains two NFkB binding sites which upregulate gene transcription (Musikacharoen et al., 2001). Inhibition of NFkB also results in lowered DC maturation, confirming an important role for this transcription factor in maturation (Rescigno et al., 1998). It appears likely that inhibition of TLR2 upregulation and maturation by bacterial antigens is related to NFkB, since EGCG inhibits NFkB p65 translocation in addition to MAPKs such as MAPKs y2, p38 and JNK. It is not yet clear whether EGCG inhibits NFkB directly or indirectly, affecting an upstream component of the TLR4 signaling pathways, which then leads to inhibition of TLR2 expression.

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