Saliva contains a number of proteins and glycoproteins that protect oral tissues, but little is known about the role of human saliva in innate immunity. Here we showed that human major salivary gland cells constitutively expressed a bacterial pattern recognition receptor, CD14, by immunohistochemistry. Human salivary gland cells in culture express CD14 mRNA and a 55-kDa CD14 protein in, but not on the cells, and secrete a soluble form with the same molecular mass. Human whole saliva contains a 55-kDa CD14, and the concentration of parotid saliva was 10-fold higher than whole saliva, which is comparable to that of serum CD14. Levels of CD14 in unstimulated whole and parotid saliva were unchanged before and after a meal and between unstimulated and stimulated saliva, indicating that saliva CD14 is constitutively secreted into the oral cavity. In contrast, lipopolysaccharide (LPS)-binding protein was below the detectable level. The saliva CD14 is functionally active in that it mediated the activation of CD14-lacking intestinal epithelial cells by LPS in a Toll-like receptor 4-dependent manner. These results suggested that saliva CD14 is important for the maintenance of oral health and possibly intestinal homeostasis.Saliva, a complex mix of fluids from major (parotid, submandibular, and sublingual) and minor salivary glands, is a most valuable oral fluid that is critical to the preservation and maintenance of oral health. In addition to containing about 99% water, saliva contributes to (i) the lubrication and protection of oral tissues, acting as a barrier against irritants; (ii) buffering and clearance; (iii) the maintenance of tooth integrity; and (iv) taste and digestion (15). Whole saliva also contains a number of antimicrobial agents, secretory immunoglobulin (IgA), proteins (glycoproteins, statherins, agglutinins, histidine-rich proteins, and proline-rich proteins), mucins, lactoferrin, enzymes (lysozyme and peroxidase), and antimicrobial peptides (10, 27). The concerted action of these agents is thought to provide a multifunctional protective network against microorganisms.CD14 is a 55-kDa glycosylphosphatidylinositol-anchored glycoprotein that is expressed mainly on the surface of monocytes and macrophages (9). CD14 functions as a bacterial pattern recognition receptor for many bacterial components in the innate immune response to bacterial invasion (18, 30). Recently, the family of Toll-like receptors (TLRs) were found to be essential molecules for microbial recognition in innate immunity; e.g., TLR2 acts as a receptor for peptidoglycan, zymosan, and lipoproteins and TLR4 acts as a receptor for lipopolysaccharide (LPS), taxol, and heat shock protein 60 (1). CD14 mediates sensitive responses to LPS by facilitating interaction with TLR4 in association with MD-2 (1). CD14 also exists in serum (4) and milk (5, 13) as a soluble form (sCD14). It has been reported that sCD14 in serum decreases cellular responses to LPS by transferring cell-bound LPS to serum lipoproteins and lactoferrin (3,12) and that sCD14 at a...