Anti-inflammatory function of secretory leukocyte protease inhibitor

Abstract

Macrophages respond to lipopolysaccharide (LPS) by producing a battery of alarm signals and defense molecules, a response that can be beneficial or detrimental to the host depending on its scale. To explore the regulation of LPS response, we compared cell lines from two strains of mice congenic for a locus markedly affecting LPS sensitivity. Differential display detected a transcript expressed in a macrophage cell line derived from LPS-hyporesponsive mice (Lps^d ) but not in macrophages derived from congenic LPS-responsive mice (Lpsⁿ ). The cloned cDNA encodes a protein homologous to human secretory leukocyte protease inhibitor (SLPI), previously regarded as an epithelial cell-derived inhibitor of leukocyte serine proteases. In macrophages, SLPI production correlates inversely with response to LPS. Phagocytes are important sources of SLPI. Besides LPS, taxol, lipoteichoic acid (LTA) and two anti-inflammatory cytokines, IL-10 and IL-6, are capable of inducing SLPI expression in macrophages. Stable transfection with SLPI suppresses the LPS- and LTA-induced production of nitric oxide and TNFα by macrophages. An anti-inflammatory role for macrophage-derived SLPI seems likely based on the following: (i) the slowly increasing production of SLPI in response to constituents of Gram-negative and Gram-positive bacteria; (ii) its induction both as a direct response to LPS and as a response to anti-inflammatory cytokines (IL-6 and IL-10) induced by LPS; and (iii) its ability to suppress the production of pro-inflammatory products by macrophages stimulated with constituents of both Gram-positive and Gram-negative bacteria.

References

Sultzer BM Genetic control of leucocyte responses to endotoxin. Nature 1968; 219: 1253—1254.

Watson J. , Largen M. , McAdam KP. Genetic control of endotoxic responses in mice. J Exp Med 1978; 147: 39—49.

Liang P. , Pardee AB Differential display of eukaryotic messenger RNA by means of the polymerase chain reaction. Science 1992; 257: 967—971.

Jin FY , Nathan C. , Radzioch D. , Ding A. Secretory leukocyte protease inhibitor: a macrophage product induced by and antagonistic to bacterial lipopolysaccharide. Cell 1997; 88: 417—426.

Thompson RC , Ohlsson K. Isolation, properties, and complete amino acid sequence of human secretory leukocyte protease inhibitor, a potent inhibitor of leukocyte elastase. Proc Natl Acad Sci USA 1986; 83: 6692—6696.

Fink E. , Nettelbeck R. , Fritz H. Inhibition of mast cell chymase by eglin c and antileukoprotease (HUSI-I). Indications for potential biological functions of these inhibitors. Biol Chem Hoppe Seyler 1986; 367: 567—571.

Ohlsson K. , Bergenfeldt M. , Bjork P. Functional studies of human secretory leukocyte protease inhibitor. Adv Exp Med Biol 1988; 240:123—131.

Hiemstra PS , Maassen RJ , Stolk J. , Heinzel-Wieland R. , Steffens GJ , Dijkman JH Antibacterial activity of antileukoprotease. Infect Immun 1996; 64: 4520—4524.

McNeely TB , Dealy M. , Dripps DJ , Orenstein JM , Eisenberg SP , Wahl SM Secretory leukocyte protease inhibitor: a human saliva protein exhibiting anti-human immunodeficiency virus 1 activity in vitro. J Clin Invest 1995; 96: 456—464.

10.

Abe T. , Kobayashi N. , Yoshimura K. et al. Expression of the secretory leukoprotease inhibitor gene in epithelial cells. J Clin Invest 1991; 87: 2207—2215.

11.

Bohm B. , Aigner T. , Kinne R. , Burkhardt H. The serine-protease inhibitor of cartilage matrix is not a chondrocytic gene product. Eur J Biochem 1992; 207: 773—779.

12.

Jin FY , Nathan CF , Radzioch D. , Ding A. Lipopolysaccharide-related stimuli induce expression of the secretory leukocyte protease inhibitor, a macrophage-derived lipopolysaccharide inhibitor. Infect Immun 1998; 66:2447—2452.

13.

Marshall JC , Cook DJ , Christou NV , Bernard GR , Sprung CL , Sibbald WJ Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome. Crit Care Med 1995; 23:1638—1652.