SLPI (green) enters the nucleus (red) of monocytes and competes with NF-B for binding to gene promoters.

But SLPI's protective function is not limited to defusing dangerous proteases. SLPI is also a potent antimicrobial peptide (akin to defensins) and an antiinflammatory agent. This group and others have shown that SLPI's antiinflammatory activity stems in part from its ability to inhibit the degradation of IBß—an inhibitor protein that binds to cytoplasmic NF-B. The importance of SLPI in limiting inflammation is evident in SLPI-deficient mice, which succumb to endotoxic shock in response to normally sublethal doses of bacterial lipopolysaccharide.

Here, Taggart and colleagues show that SLPI also targets NF-B in the nucleus, where SLPI binds to B binding sites on gene promoters, displacing the NF-B protein p65. This competition inhibits the production of inflammatory cytokines such as interleukin (IL)-8 and TNF. Thus, any NF-B protein that circumvents SLPI's roadblock in the cytoplasm would likely encounter a second wave of SLPI-mediated resistance in the nucleus.

The preferential production of this multifunctional protein at mucosal surfaces probably reflects the importance of preventing excessive immune activation in tissues barraged by environmental pathogens. Whether SLPI-mediated inhibition is defective in individuals prone to chronic inflammatory diseases of the mucosa, such as asthma or inflammatory bowel disease, remains to be tested.