Jpn. J. Infect. Dis., 54, 209-219, 2001

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Invited Review

Regulation of Innate Immune Responses by Toll-Like Receptors

Kiyoshi Takeda^1,2 and Shizuo Akira^1,2*

¹Department of Host Defense, Research Institute for Microbial Diseases, Osaka University and ²Solution-oritented Research for Science and Technology, Japan Science and Technology Corporation, Yamada-oka 3-1, Suita, Osaka 565-0871, Japan

(Received October 11, 2001)

CONTENTS:
1. Introduction
2. Innate immune responses in Drosophila
3. Innate immune activation by Toll-like receptors (TLRs)
  3-1. Identification of TLRs in mammals
  3-2. TLR4 is a signaling component of the lipopolysaccharide (LPS) receptor
  3-3. The TLR family is responsible for recognition of microbial components
4. Signaling pathway via TLRs
  4-1. Comparison of signaling pathways with Drosophila Toll and mammalian TLR
  4-2. MyD88 is a critical component in TLR signaling
  4-3. MyD88-independent TLR signaling
5. Suppression of innate immune cell activity by microbial components
  5-1. Mechanism for LPS tolerance
  5-2. Microbial components induce LPS tolerance
6. Future prospects

SUMMARY: Innate immune response in Drosophila is mediated by signaling through Toll receptors. In mammals, Toll-like receptors (TLRs), comprising a large family, recognize a specific pattern of microbial components. So far, the roles of TLR2, TLR4, TLR5, TLR6, and TLR9 have been revealed. The recognition of microbial components by TLRs leads to activation of innate immunity, which provokes inflammatory responses and finally the development of adaptive immunity. The inflammatory response depends on a TLR-mediated MyD88-dependent cascade. However, there seems to exist additional cascades in TLR signaling. In the case of TLR4 signaling, an MyD88-independent pathway is now being characterized. In addition to the activation of innate immune responses, TLR-mediated signaling leads to suppression of the activity of innate immune cells, represented by "lipopolysaccharide (LPS) tolerance". Progress in elucidating the molecular mechanisms for LPS tolerance has been made through the analysis of TLR-mediated signaling pathways. Thus, the activity for innate immune responses is known to be finely regulated by TLRs.

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