Secretory leucoprotease inhibitor binds to NF-κB binding sites in monocytes and inhibits p65 binding

Abstract

Secretory leucoprotease inhibitor (SLPI) is a nonglycosylated protein produced by epithelial cells. In addition to its antiprotease activity, SLPI has been shown to exhibit antiinflammatory properties, including down-regulation of tumor necrosis factor α expression by lipopolysaccharide (LPS) in macrophages and inhibition of nuclear factor (NF)-κB activation in a rat model of acute lung injury. We have previously shown that SLPI can inhibit LPS-induced NF-κB activation in monocytic cells by inhibiting degradation of IκBα without affecting the LPS-induced phosphorylation and ubiquitination of IκBα. Here, we present evidence to show that upon incubation with peripheral blood monocytes (PBMs) and the U937 monocytic cell line, SLPI enters the cells, becoming rapidly localized to the cytoplasm and nucleus, and affects NF-κB activation by binding directly to NF-κB binding sites in a site-specific manner. SLPI can also prevent p65 interaction with the NF-κB consensus region at concentrations commensurate with the physiological nuclear levels of SLPI and p65. We also demonstrate the presence of SLPI in nuclear fractions of PBMs and alveolar macrophages from individuals with cystic fibrosis and community-acquired pneumonia. Therefore, SLPI inhibition of NF-κB activation is mediated, in part, by competitive binding to the NF-κB consensus-binding site.

Estradiol selectively regulates innate immune function by polarized human uterine epithelial cells in culture

“…In other studies, SLPI-deficient mice were reported to be more sensitive to LPS-induced shock; their macrophages had higher IL-6 and NF-kB activity, suggesting that SLPI attenuates excessive inflammatory responses. 49 Taggart, Greene, and co-workers 50,51 demonstrated that SLPI downregulates TNF-α expression induced by LPS by inhibiting degradation of IkBp and binds directly to NF-kB in a site-specific manner. More recently, E 2 was found to protect against Human Immunodeficiency Virus Tat protein-induced inflammatory reactions in vascular endothelium by blocking NF-kB signaling.…”

Innate immunity and disorders of the female reproductive tract

“…In vitro, overexpression of SLPI suppresses NFKB activation (Jin et al 1997, Sano et al 2003, Henriksen et al 2004. It can prevent proteosome-dependent IkBb degradation (Lentsch et al 1999) and also directly bind to NFKB consensus sites on DNA, inhibiting transcription (Taggart et al 2005). Wound healing and tissue remodelling are other processes involving the anti-leukoproteinases.…”

The Effect of Liposome Encapsulation on the Pharmacokinetics of Recombinant Secretory Leukocyte Protease Inhibitor (rSLPI) Therapy after Local Delivery to a Guinea Pig Asthma Model

“…Along with its extracellular antiprotease activity, rSLPI also exhibits intracellular activity in alveolar macrophages as it is here that it exerts an anti-inflammatory activity by binding to nuclear factor (NF)-kappa B binding sites (Taggart et al, 2005). The encapsulation of rSLPI within liposomes that are specifically taken up AMs can therefore be regarded as a targeted carrier system.…”