Therapeutic Targeting of Toll-Like Receptors in Gastrointestinal Inflammation

Shunji      Ishihara; Mohammad   A.K.   Rumi; Cesar-F.      Ortega-Cava; Hideaki      Kazumori; Yasunori      Kadowaki; Norihisa      Ishimura; Yoshikazu      Kinoshita

doi:10.2174/138161206778743448

Abstract

Toll-like receptors (TLRs) are sensors of microbial products that initiate host defense responses in multicellular organisms. They are mainly linked to innate immunity and bridging to adaptive immunity, signaling through different TLRs responsible for a wide range of biological responses. The intracellular signaling pathways through Toll/interleukin- 1 receptor (IL-1R) domains result in recruitment of the cytoplasmic adaptor molecules, with subsequent activation of a signaling cascade leading to nuclear factor-κ B (NF-κB). TLR-signaling induces host inflammatory response and the inflammation becomes more severe in the absence of several extra and intra cellular negative regulators of TLR-signaling. In the intestine, TLR-dependent activation of NF-κB plays a vital role in maintaining epithelial homeostasis as well as regulating infections and inflammation, while dysregulation of TLR-signaling is associated with the pathogenesis of inflammatory bowel diseases (IBD). Recent findings regarding innate immunity-mediated regulation of intestinal pathophysiology prove that development of new drugs targeting TLRs including antagonists of TLR-signaling and agonists of their negative regulators has a potential impact on therapeutic strategies for intestinal inflammatory diseases.

Keywords: CRX-526, TLR expression, pro-inflammatory, Endotoxin, inflammatory bowel diseases (IBD)

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