Secretory leucoprotease inhibitor (SLPI) is an 11.7-kDa nonglycosylated serine protease inhibitor produced by the mucosal surfaces of epithelial cells, macrophages, and neutrophils (1
). It provides significant protection for the respiratory epithelial surfaces against neutrophil elastase (NE) released from activated or disintegrating neutrophils (6
). SLPI also has antibacterial, antiviral, and anti-inflammatory properties (10
). Previously we have shown that SLPI, but not oxidized SLPI, can inhibit lipopolysaccharide (LPS)-induced NF-κB activation (26
). It does this by inhibiting degradation of IRAK, IκBα, and IκBβ. These findings prompted us to investigate whether SLPI may have broader anti-inflammatory effects, such as the ability to inhibit responses induced by other microbial components, in particular lipoteichoic acid (LTA).
Toll-like receptors (TLRs) belong to a large family of homologous proteins, TLR1 to TLR10 (4
), that play an important role in innate immune defenses due to their ability to recognize and discriminate a diverse array of microbial components. Following activation by their cognate ligands, TLRs initiate a conserved intracellular signaling cascade to activate NF-κB and to induce expression of NF-κB-regulated genes (4
). LTA signals via TLR2, while TLR4 is the recognized mammalian receptor for LPS (11
). TLR2 is also activated by a number of other microbial components, including bacterial lipopeptides and yeast zymosan (17
), and can heterodimerize with TLR1 and -6 to enhance its sensitivity to different stimuli (22
). Of the known ligands for other TLRs, double-stranded RNA, flagellin, and unmethylated CpG dinucleotides are recognized by TLR3, -5, and -9, respectively. TLR7 and -8 can be regulated by imidazoquinoline compounds, suggesting an antiviral role (for recent reviews see references 2
), while activators of TLR10 have yet to be identified.