Disease relevance of Slpi

• Impaired healing states are characterized by excessive proteolysis and often bacterial infection, leading to the hypothesis that SLPI may have a role in this process [1].
• In addition, the effects of exogenously administered and endogenous SLPI on liver and lung injury induced by hepatic ischemia and reperfusion were evaluated [2].
• Therapeutic effects of benzoxazinorifamycin KRM-1648 administered alone or in combination with a half-sized secretory leukocyte protease inhibitor or the nonsteroidal anti-inflammatory drug diclofenac sodium against Mycobacterium avium complex infection in mice [3].
• The slow attainment of maximal induction of SLPI by LPS in vitro was mimicked by infection with Pseudomonas aeruginosa in vivo, where SLPI expression in the lung peaked at 3 days [4].
• Identification and cloning of a novel isoform of mouse secretory leukocyte protease inhibitor, mSLPI-beta, overexpressed in murine leukemias and a highly liver metastatic tumor, IMC-HA1 cells [5].

High impact information on Slpi

• IFN gamma suppressed expression of SLPI and restored LPS responsiveness to SLPI-producing cells [6].
• Transfection of macrophages with SLPI suppressed LPS-induced activation of NF-kappa B and production of nitric oxide and TNF alpha [6].
• LPS-hyporesponsive cells, primary macrophages, and polymorphonuclear leukocytes transcribed secretory leukocyte protease inhibitor (SLPI), a known epithelial cell-derived inhibitor of leukocyte serine proteases [6].
• Secretory leukocyte protease inhibitor: a macrophage product induced by and antagonistic to bacterial lipopolysaccharide [6].
• Thus, SLPI is an LPS-induced IFN gamma-suppressible phagocyte product that serves to inhibit LPS responses [6].

Chemical compound and disease context of Slpi

• To clarify the functions of SLPI in bacterial infections, we generated SLPI-deficient mice (SLPI(-/-) mice) and analyzed their response to experimental endotoxin shock induced by lipopolysaccharide (LPS) [7].

Biological context of Slpi

• Delayed cutaneous wound healing in mice lacking solute carrier 11a1 (formerly Nramp1): correlation with decreased expression of secretory leukocyte protease inhibitor [8].
• Our results suggest that SLPI attenuates excessive inflammatory responses and thus assures balanced functioning of innate immunity [7].
• In parallel to the observed cutaneous healing phenotype, an absence of SLPI results in markedly impaired oral wound healing associated with increased inflammation and raised elastase activity [9].
• Four single amino acid substitution mutants of SLPI, M73G, M73F, M73E and M73K, were generated [10].
• This phosphorylation modulates its association with HDAC1, -3, and -6 and attenuates its oncogenicity by selectively controlling the expression of a subset of newly identified target genes such as SLPI and Cxcl1 [11].

Anatomical context of Slpi

• Induction of SLPI in excisional cutaneous wounds and, most importantly, in macrophages infiltrating these wounds was significantly higher in Nramp1 WT mice compared to KO mice [8].
• In this setting, IFN-gamma was a potent stimulator of matrix metalloproteinases (MMPs), cathepsins, and CXC and other chemokines while inhibiting secretory leukocyte proteinase inhibitor (SLPI) [12].
• SLPI also affects B cell function [7].
• Macrophage cell lines were established from RAW264.7 cells to stably express each SLPI mutant [10].
• RESULTS: Intravenous infusion of SLPI reduced liver and lung damage and diminished neutrophil accumulation in both organs [2].

Associations of Slpi with chemical compounds

• Despite the slowly mounting and prolonged response, early expression of SLPI mRNA was cycloheximide resistant [4].
• Mouse secretory leukocyte protease inhibitor (SLPI) was recently characterized as a lipopolysaccharide (LPS)-induced product of macrophages that antagonizes their LPS-induced activation of NF-kappaB and production of NO and tumor necrosis factor (TNF) (F. Y. Jin, C. Nathan, D. Radzioch, and A. Ding, Cell 88:417-426, 1997) [4].
• The suppressive effects of ES products were not restored by the treatment of indomethacin or anti-IL-10 antibody, and the ES products did not induce mRNA expression of secretory leukocyte protease inhibitor [13].
• Released fluvastatin increased human mesenchymal stem cell (hMSC) gene expression of CBFA1, ALP, and COL I by 34-fold, 2.6-fold, and 1.8-fold, respectively, after 14 days of in vitro culture [14].
• Clinical chemistry parameters were altered in females only and included a decrease in creatinine (low dose), an increase in BUN/creatinine ratio (mid dose), and an increase in ALP (high dose) [15].

Regulatory relationships of Slpi

• Taken together, these results suggest for the first time that Nramp1 controls macrophage SLPI mRNA and protein expression, and can also have an important effect on the kinetics of wound healing [8].

Other interactions of Slpi

• The altered inflammatory profile involves enhanced activation of local TGF-beta in Slpi-null mice [1].
• Secretory leukoprotease inhibitor (SLPI) protects tissue against the destructive action of neutrophil elastase at the site of inflammation [7].
• This may be explained in part by our observation that SLPI(-/-) macro-phages show higher interleukin 6 and high-mobility group (HMG)-1 production and nuclear factor kappaB activities after LPS treatment than do SLPI(+/+) macrophages [7].
• Like secretory leukocyte protease inhibitor, MMP-9 was expressed constitutively in the Lpsd macrophage cell line and not in the Lpsn cell line [16].

Analytical, diagnostic and therapeutic context of Slpi

• SLPI mRNA was detectable in macrophages by Northern blot analysis within 30 min of exposure to LPS but levels peaked only at 24 to 36 h and remained elevated at 72 h [4].
• Results Expression of TLR1-9 as well as beta-defensins 1, 2 and 4 and SLPI by uterine and vaginal tissues was demonstrated by RT-PCR. beta-Defensins and SLPI expression was greater in the vagina than in the uterus [17].

References