Given the importance of TLR signaling to the development of mucosal inflammation, it is understandable that a great deal of interest exists in the development of agents that can interfere with TLRsignaling pathways. Such an antiinflammatory approach may have particular relevance in the case of epithelial inflammation, due to ready access of the gastrointestinal, pulmonary, and urinary mucosa through ingestion, inhalation, or instillation via catheter delivery methods. Considerable attention has been placed on developing agents that are capable of modulation of the TLR4mediated response, in particular through manipulation of the lipid A moiety of LPS. Such lipid A mimetics, termed aminoalkyl glucosaminide phosphates (AGPs), have been demonstrated to reduce inflammation in experimental models of systemic sepsis induced by intravenous injection of Listeria monocytogenes (116) , pulmonary infection after intranasal administration of influenza virus (116) , murine models of colitis including DSS-induced colitis (117) , and spontaneous colitis in multidrug resistance gene 1a-deficient mice (117) . In parallel studies, soluble TLRs may reduce TLR signaling by binding to circulating ligands, rendering them unable to initiate pro-inflammatory signaling. Brandl et al. demonstrated that the synthetic molecule "LPS-Trap" was capable of blocking LPS-mediated macrophage activation in vitro by fusing MD-2 to the C-terminus of a soluble form of TLR4 (118) . Iwami et al. cloned an alternatively spliced soluble murine TLR4 (smTLR4) that, when transfected into murine macrophages, was secreted and inhibited LPS-mediated macrophage NF-κB activation and TNF-α release in vitro (119) . In addition, TLR-signaling intermediates have been targeted chemically to minimize the host inflammatory response. The synthetic peptide-mimetic compound ST2825 prevents MyD88 homodimer formation leading to an inhibition in MyD88dependent signaling, and prevents TLR9dependent inflammation in vivo (120) . A cyclohexene derivative, TAK-242, prevents TLR4 activation and was found to reduce the cytokine response to endotoxemic shock in mice (121, 122) . The Vaccinia virus protein A52R also reduces the TLR-mediated response by interacting with IRAK2 and TRAF6, and was found to reduce the cytokine response in an animal model of infectious otitis media (123, 124) and to increase survival in models of endotoxemia (125) .