[23, 24] LPS is a potent activator of Mφ and other dendritic cells. After being released into the blood stream or other body fluids, LPS is

immediately captured by LPS-binding protein (LBP) that delivers LPS to TLR4 or CD14. CD14 lacks a trans-membrane domain and so is incapable of transducing signals.[25] Both the positional cloning of the locus responsible for LPS hypo-responsiveness in C3H/HeJ mice and the CDK inhibitor generation of TLR4 knockout mice have shown that TLR4 is essential for LPS signaling.[16, 21] In addition, the interaction of LPS with TLR4 requires another molecule, MD-2, which associates with the extracellular domain of TLR4. Once TLR are activated, the intracellular signaling pathways are very similar between insects and mammals. In mammals, TLR4 signaling involves activation of one or more of the adaptor proteins. The adaptors relevant to TLR4 signaling are known as MyD88 (myeloid differentiation factor 88), TIRAP (TIR domain-containing adaptor protein), TRIF (TIR-domain containing-adaptor inducing interferon-β) and TRAM (TRIF-related adaptor molecule).[4, 26] Most TLR act

through MyD88 alone or through both MyD88 and TIRAP, which leads to the production of different pro-inflammatory cytokines. MyD88 is an adaptor molecule that recruits the kinase IRAK (IL-1 receptor-associated kinase) to the TLR4 receptor complexes after stimulation with LPS. The lipopeptide activation of nuclear factor (NF)-κB Ergoloid and MAP (mitogen-activated protein) high throughput screening kinases, as mediated by TLR2, is completely abolished in TLR2-depleted or MyD88-deficient Mφ. By contrast, LPS

activation of MAP kinases and NF-κB remains intact in MyD88-deficient Mφ. This indicates that LPS response is mediated by both MyD88-dependent and MyD88-independent pathways, each of which leads to the activation of MAP kinases and NF-κB. The MyD88-dependent pathway is essential, however, for the inflammatory response mediated by LPS. TIRAP has a crucial role in the MyD88-dependent signaling pathway shared by TLR2 and TLR4. Recent studies have shown that the MyD88-independent pathway for TLR4 operates through different adaptor molecules, TRIF and TRAM, activates interferon (IFN) regulatory factor 3 (IRF-3), upregulates co-stimulatory molecules, and leads to the subsequent induction of type I interferon such as IFN-β, nitric oxide synthase (iNOS) and IFN-inducible protein (IP-10).[4, 26] It is important to remember that in addition to activation of IRF-3, the MyD88-independent pathway also elicits delayed activation of NF-κB. Studies are still limited on the MyD88-independent pathway. TLR4 signaling pathways are shown in Figure 1. Unlike other TLR, TLR3 uses only one adaptor protein, TRIF, whose activation leads to IRF-3 translocation to the nucleus.