The Intracellular Signaling Pathways of Inflammatory Stress

Abstract

In severe sepsis the host is overwhelmed partly by microorganisms and their products, and partly by inflammatory cytokines produced in response to the infection. The initial defense against microbial invasion, innate immunity, is mounted by mononuclear phagocytes which are scattered through most tissues. They have evolved receptors that detect microbial products. These have been called pattern recognition receptors and they detect unusual chemical structures not found in mammalian cells, such as lipopolysaccharides (LPS), lipoteichoic acid (LTA), peptidoglycans, muramyl peptides, mannans, unmethylated CpG motifs in bacterial DNA and so on [1]. The best known is CD14, which binds LPS, and probably other bacterial products. How the microbial substances signal to the interior of the cell has become clearer with the discovery of the Toll-like receptors (TLR) [2–4]. These are transmembrane proteins related to the interleukin (IL)-l receptor. The Toll prototype is found in Drosophila where it plays roles in development and protection against fungi. In mammals TLRs are activated by bacterial molecules (e.g., LPS bound to CD14), and signal by apparently the same pathways as IL-1. The molecule that mediates LPS and LTA signaling is TLR4, while TLR2 is involved in recognition of peptidoglycan of Gram-positive organisms. To what extent TLRs themselves bind microbial products is not yet clear; in the case of LPS the activation of TLR4 is indirect, the ligand for the TLR is not known. A very recent discovery is that TLR9 signals recognition of bacterial DNA [5]. The ligands and functions of the other TLRs are being searched for by many laboratories.