LPS is the major constituent of the outer membrane of Gram-negative bacteria and is one of the most potent TLR ligands. CD14 together with LBP plays an essential role in binding of LPS to the TLR4/MD-2 complex [7] . LBP, which, among others, is present in the bloodstream and BAL fl uid [8] , binds to LPS aggregates and transfers LPS monomers to CD14. CD14 associates with TLR4/ MD-2 and transfers the LPS monomer to this complex [7] . Likewise, sCD14 is able to mediate LPS-activation of cells with low membrane CD14 expression, such as epithelial and endothelial cells [9] . However, at high con cen trations, LBP and sCD14 are also able to downregulate LPS-induced responses by transfer of LPS to lipoproteins for subsequent removal [10] . Recent data indicate that LPS is bound by MD-2 within the TLR4/ MD-2 complex [11] and that subsequent conformational changes in TLR4 lead to reorganization of its cytoplasmic domain, enabling the recruitment of the adaptor proteins, myeloid diff erentiation primary-response protein 88 (MyD88) and TIR-domain-containing-adaptorprotein-inducing-inter feron (IFN)-β (TRIF) [12] . Th ese adaptors initiate signal transduction to the nucleus by activation of nuclear factor (NF)-κB and IFN regulatory transcription factor (IRF)-3, leading to the production of cytokines that regulate infl ammatory cells [12] . In macrophages, TRIF-dependent signaling is essential for the expression of the majority of LPS-induced genes, including IFN-α/β. CD14, which lacks an intracellular domain for signal transduction, is expressed on the surface of alveolar macrophages, infi ltrating monocytes and neutrophils, and at lower levels also on epithelial and endothelial cells in the lung. CD14 recognizes and binds various structures from invading microbes, such as lipopolysaccharide (LPS) from Gram-negative bacteria, lipoteichoic acid (LTA) from Gram-positive bacteria, lipoarabinomannan (LAM) from mycobacteria, viral double stranded (ds) RNA and F glycoprotein (F-gp) from respiratory syncytial virus (RSV). CD14 subsequently transfers these bound components to Toll-like receptors (TLR) which than trigger cell activation. Binding of LPS to CD14 is regulated by additional accessory receptors in the lung, including LPS-binding protein (LBP) and a number of surfactant proteins (SP). Furthermore, soluble CD14 (sCD14) enhances LPS-induced activation of cells with low CD14 expression. Depending on the microbe and the PAMPs it expresses, CD14-amplifi ed responses can either be benefi cial to the host by induction of an adequate infl ammatory and immune response to eradicate the invading microbe, or detrimental to the host by excessive infl ammation and/or dissemination of the pathogen. Recently, it was reported that, in the absence of CD14, the TLR4/MD-2 complex can distinguish between diff erent chemotypes of LPS [13] . Smooth LPS is synthesized by most Gram-negative bacteria and consists of three modules: Th e lipid A moiety, a core poly saccharide, and an O-polysaccharide of variable length (made up of 1 to over 50 monosaccharide units) [7] . Gram-negative bacteria that fail to add the core polysaccharide or the O-polysaccharide chain to the lipid A moiety produce `rough' LPS, named after the rough morphology of the colonies these bacteria form. Lipid A, the bioactive part of both smooth and rough LPS, is responsible for most of the pathogenic eff ects in Gram-negative bacterial infections [7, 12] . Murine macrophages lacking CD14 secreted equal amounts of tumor necrosis factor-α (TNF) to macrophages expressing CD14 upon stimulation with rough LPS, but failed to secrete TNF in response to smooth LPS, an eff ect which was reversed by addition of sCD14 [13] . Moreover, macrophages lacking CD14 failed to secrete IFN-α/β in response to either rough or smooth LPS. Th ese fi ndings indicate that CD14 is required for activation of the TLR4/TRIF pathway by either smooth or rough LPS, and required for the activation of TLR4/ MyD88 pathway by smooth but not by rough LPS [13] . In addition to LPS, CD14 also facilitates TLR4 activation by other PAMPs including certain viral components [13, 14] .