Fever Promotes TLR4 Expression And Signaling In Dendritic Cells

Fever is a complex physiological response to infection, inflammation, and trauma. There are two types of cytokines responsible for the generation of fever. Endogenous pyrogens are cytokines that induce fever and include interleukin (IL)-l, IL~6, IL-8, macrophage-inflammatory protein-la (MIP-1 a), and interferon- Y. The other types of cytokines are endogenous antipyretics, which limit the magnitude and duration of fever and include such substances as IL—10. Other substances, such as tumor necrosis factor-a (TNF-a), have been shown to have pyrogenic and antipyretic properties, depending on the experimental conditions.At present, fever was thought to be a beneficial physiological response against bacterial, fungal, and viral infections. In addition, fever can accelerate resolution of microbial infection, shorten disease duration and improve survival. However, the mechanisms by which fever regulates immune response remain undefined. Previous studies provide evidence that fever range temperature treatment enhances humoral and cellular immune response. Recent findings showed that fever range temperatures induces maturation of dendritic cells (DC) through induction of HSP90. Fever-like temperature regulates DC activation and enhances epidermal langerhans cell migration from skin explants. Furthermore, fever range temperatures stimulate lymphocyte homing tosecondary lymphoid tissue by increasing L-selection-dependent adhesive interactions between circulating lymphocytes and specialized high endothelial venules. Fever range temperatures augment innate immunity by enhancing neutrophil activation and enhancing reactive oxygen intermediates and NO release. In mice, fever ranger temperature increases LPS-induced cytokine production and improves survival upon bacterial challenge compared with normal core body temperature.The family of Toll-like receptors (TLRs) has a crucial role in the detection of microbial infection in mammalian and insect. These receptors recognize conserved products of microbial metabolism named pathogen associated molecular patterns (PAMPs), and initiate innate immune responses. So far, eleven mammalian toll-like receptors have been identified. The TLRs family was characterized by the present of an extracellular domain containing leucine-rich repeats and a cytoplasmic Toll/lL-1 receptor domain similar to that IL—1 receptor family. TLRs are expressed in a variety of cell types, mostly predominantly in immune system, including macrophages, DC, neutrophils and lymphocytes.Among the eleven mammalian TLRs identified, TLR4 has been identified as the receptor for bacterial LPS, a very potent immuno-activator. In addition, TLR4 is implicated in the recognition of pacific yew product taxol, fusion protein of respiratory virus and envelope protein of mouse mammary virus. Furthermore, TLR4 has been shown to be involved in the recognition of endogenous ligands, such as heat shock proteins (HSP60 and HSP70), the extra domain A of fibronectins, oligosaccharidcs of hyaluronic acid, heparan sulfate and fibrinogen.Dendritic cells (DCs) are professional antigen-presenting cells that bridge innate and adaptive immunity. They express several toll-likereceptors, which mediate the recognition of pathogen-associated molecular patterns (PAMP). Among the TLRs expressed by DC, TLR4 senses the gram-negative bacteria infection by recognition LPS, an integral component of the outer gram-negative bacteria, and then can induce DC to produce inflamantary cytokines such as TNF-a, IL—12 and IL-1O. In addition, TLR4 mediated LPS signaling induce the maturation of DC. Activationvs of NF-KB and MAPK pathways play important role in the TLR4 signaling, leading to the expression of the pro-inflammatory genes.Although fever was thought to associate with improved survival and shortened disease duration in infection, the mechanisms of these beneficial responses remain unclear. Responsibility of immune cells to PAMPs is correlated with the level of TLR expression. Because DC can express several kinds of TLRs such as TLR4 and play very important rol...