Abstract
Secretory leukocyte protease inhibitor (SLPI) is a serine protease inhibitor found in fluids lining mucosal surfaces. In addition to its primary function as an antiprotease, SLPI may also influence cellular functions associated with enzyme synthesis and retroviral infection. In this study, SLPI was examined for its effect on signaling events involved in the production of matrix metalloproteinases (MMPs) by monocytes. Addition of SLPI before stimulation with concanavalin A or LPS resulted in a significant inhibition of monocyte prostaglandin H synthase-2 (PGHS-2), a pivotal enzyme in the PGE2-cAMP dependent pathway of monocyte MMP synthesis. Suppression of PGHS-2 was detected with 0.1 microg/ml of SLPI with a substantial inhibition at 1 and 10 micro/ml. Attenuation of PGHS-2 by SLPI was accompanied by decreased production of PGE2 resulting in the suppression of interstitial collagenase (MMP-1) and gelatinase B (MMP-9) that was reversed by PGE2 or Bt2cAMP. The inhibitory effect of SLPI was largely independent of its antiprotease activity because SLPI muteins, with significantly lower antiprotease activity, also suppressed the induction of PGHS-2 and MMPs. The inhibitory effects of SLPI did not involve the modulation of monokine production since TNF-alpha and IL-10 were unaffected. These findings demonstrate that SLPI also functions as a potent antiinflammatory agent by interfering with the signal transduction pathway leading to monocyte MMP production.
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- Birkedal-Hansen H., Moore W. G., Bodden M. K., Windsor L. J., Birkedal-Hansen B., DeCarlo A., Engler J. A. Matrix metalloproteinases: a review. Crit Rev Oral Biol Med. 1993;4(2):197–250. doi: 10.1177/10454411930040020401. [DOI] [PubMed] [Google Scholar]
- Busiek D. F., Baragi V., Nehring L. C., Parks W. C., Welgus H. G. Matrilysin expression by human mononuclear phagocytes and its regulation by cytokines and hormones. J Immunol. 1995 Jun 15;154(12):6484–6491. [PubMed] [Google Scholar]
- Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
- Corcoran M. L., Stetler-Stevenson W. G., Brown P. D., Wahl L. M. Interleukin 4 inhibition of prostaglandin E2 synthesis blocks interstitial collagenase and 92-kDa type IV collagenase/gelatinase production by human monocytes. J Biol Chem. 1992 Jan 5;267(1):515–519. [PubMed] [Google Scholar]
- Corcoran M. L., Stetler-Stevenson W. G., DeWitt D. L., Wahl L. M. Effect of cholera toxin and pertussis toxin on prostaglandin H synthase-2, prostaglandin E2, and matrix metalloproteinase production by human monocytes. Arch Biochem Biophys. 1994 May 1;310(2):481–488. doi: 10.1006/abbi.1994.1196. [DOI] [PubMed] [Google Scholar]
- Corcoran M. L., Stetler-Stevenson W. G. Tissue inhibitor of metalloproteinase-2 stimulates fibroblast proliferation via a cAMP-dependent mechanism. J Biol Chem. 1995 Jun 2;270(22):13453–13459. doi: 10.1074/jbc.270.22.13453. [DOI] [PubMed] [Google Scholar]
- DeWitt D., Smith W. L. Yes, but do they still get headaches? Cell. 1995 Nov 3;83(3):345–348. doi: 10.1016/0092-8674(95)90109-4. [DOI] [PubMed] [Google Scholar]
- Eisenberg S. P., Hale K. K., Heimdal P., Thompson R. C. Location of the protease-inhibitory region of secretory leukocyte protease inhibitor. J Biol Chem. 1990 May 15;265(14):7976–7981. [PubMed] [Google Scholar]
- Hayakawa T., Yamashita K., Ohuchi E., Shinagawa A. Cell growth-promoting activity of tissue inhibitor of metalloproteinases-2 (TIMP-2). J Cell Sci. 1994 Sep;107(Pt 9):2373–2379. doi: 10.1242/jcs.107.9.2373. [DOI] [PubMed] [Google Scholar]
- Hayakawa T., Yamashita K., Tanzawa K., Uchijima E., Iwata K. Growth-promoting activity of tissue inhibitor of metalloproteinases-1 (TIMP-1) for a wide range of cells. A possible new growth factor in serum. FEBS Lett. 1992 Feb 17;298(1):29–32. doi: 10.1016/0014-5793(92)80015-9. [DOI] [PubMed] [Google Scholar]
- Hla T., Neilson K. Human cyclooxygenase-2 cDNA. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7384–7388. doi: 10.1073/pnas.89.16.7384. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jacoby A. S., Melrose J., Robinson B. G., Hyland V. J., Ghosh P. Secretory leucocyte proteinase inhibitor is produced by human articular cartilage chondrocytes and intervertebral disc fibrochondrocytes. Eur J Biochem. 1993 Dec 15;218(3):951–957. doi: 10.1111/j.1432-1033.1993.tb18452.x. [DOI] [PubMed] [Google Scholar]
- Kouchi I., Yasuoka S., Ueda Y., Ogura T. Analysis of secretory leukocyte protease inhibitor (SLPI) in bronchial secretions from patients with hypersecretory respiratory diseases. Tokushima J Exp Med. 1993 Jun;40(1-2):95–107. [PubMed] [Google Scholar]
- Kujubu D. A., Fletcher B. S., Varnum B. C., Lim R. W., Herschman H. R. TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue. J Biol Chem. 1991 Jul 15;266(20):12866–12872. [PubMed] [Google Scholar]
- Lee S. H., Soyoola E., Chanmugam P., Hart S., Sun W., Zhong H., Liou S., Simmons D., Hwang D. Selective expression of mitogen-inducible cyclooxygenase in macrophages stimulated with lipopolysaccharide. J Biol Chem. 1992 Dec 25;267(36):25934–25938. [PubMed] [Google Scholar]
- McCarthy J. B., Wahl S. M., Rees J. C., Olsen C. E., Sandberg L., Wahl L. M. Mediation of macrophage collagenase production by 3'-5' cyclic adenosine monophosphate. J Immunol. 1980 May;124(5):2405–2409. [PubMed] [Google Scholar]
- McNeely T. B., Dealy M., Dripps D. J., Orenstein J. M., Eisenberg S. P., Wahl S. M. Secretory leukocyte protease inhibitor: a human saliva protein exhibiting anti-human immunodeficiency virus 1 activity in vitro. J Clin Invest. 1995 Jul;96(1):456–464. doi: 10.1172/JCI118056. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Meade E. A., Smith W. L., DeWitt D. L. Expression of the murine prostaglandin (PGH) synthase-1 and PGH synthase-2 isozymes in cos-1 cells. J Lipid Mediat. 1993 Mar-Apr;6(1-3):119–129. [PubMed] [Google Scholar]
- Mertz P. M., DeWitt D. L., Stetler-Stevenson W. G., Wahl L. M. Interleukin 10 suppression of monocyte prostaglandin H synthase-2. Mechanism of inhibition of prostaglandin-dependent matrix metalloproteinase production. J Biol Chem. 1994 Aug 19;269(33):21322–21329. [PubMed] [Google Scholar]
- O'Sullivan M. G., Chilton F. H., Huggins E. M., Jr, McCall C. E. Lipopolysaccharide priming of alveolar macrophages for enhanced synthesis of prostanoids involves induction of a novel prostaglandin H synthase. J Biol Chem. 1992 Jul 25;267(21):14547–14550. [PubMed] [Google Scholar]
- Seemüller U., Arnhold M., Fritz H., Wiedenmann K., Machleidt W., Heinzel R., Appelhans H., Gassen H. G., Lottspeich F. The acid-stable proteinase inhibitor of human mucous secretions (HUSI-I, antileukoprotease). Complete amino acid sequence as revealed by protein and cDNA sequencing and structural homology to whey proteins and Red Sea turtle proteinase inhibitor. FEBS Lett. 1986 Apr 7;199(1):43–48. doi: 10.1016/0014-5793(86)81220-0. [DOI] [PubMed] [Google Scholar]
- Shapiro S. D., Kobayashi D. K., Pentland A. P., Welgus H. G. Induction of macrophage metalloproteinases by extracellular matrix. Evidence for enzyme- and substrate-specific responses involving prostaglandin-dependent mechanisms. J Biol Chem. 1993 Apr 15;268(11):8170–8175. [PubMed] [Google Scholar]
- Stetler G., Brewer M. T., Thompson R. C. Isolation and sequence of a human gene encoding a potent inhibitor of leukocyte proteases. Nucleic Acids Res. 1986 Oct 24;14(20):7883–7896. doi: 10.1093/nar/14.20.7883. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Thompson R. C., 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 U S A. 1986 Sep;83(18):6692–6696. doi: 10.1073/pnas.83.18.6692. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vogelmeier C., Hubbard R. C., Fells G. A., Schnebli H. P., Thompson R. C., Fritz H., Crystal R. G. Anti-neutrophil elastase defense of the normal human respiratory epithelial surface provided by the secretory leukoprotease inhibitor. J Clin Invest. 1991 Feb;87(2):482–488. doi: 10.1172/JCI115021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wahl L. M., Katona I. M., Wilder R. L., Winter C. C., Haraoui B., Scher I., Wahl S. M. Isolation of human mononuclear cell subsets by counterflow centrifugal elutriation (CCE). I. Characterization of B-lymphocyte-, T-lymphocyte-, and monocyte-enriched fractions by flow cytometric analysis. Cell Immunol. 1984 May;85(2):373–383. doi: 10.1016/0008-8749(84)90251-x. [DOI] [PubMed] [Google Scholar]
- Wahl L. M., Lampel L. L. Regulation of human peripheral blood monocyte collagenase by prostaglandins and anti-inflammatory drugs. Cell Immunol. 1987 Apr 1;105(2):411–422. doi: 10.1016/0008-8749(87)90088-8. [DOI] [PubMed] [Google Scholar]
- Wahl L. M., Olsen C. E., Sandberg A. L., Mergenhagen S. E. Prostaglandin regulation of macrophage collagenase production. Proc Natl Acad Sci U S A. 1977 Nov;74(11):4955–4958. doi: 10.1073/pnas.74.11.4955. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wahl S. M., McCartney-Francis N., Hunt D. A., Smith P. D., Wahl L. M., Katona I. M. Monocyte interleukin 2 receptor gene expression and interleukin 2 augmentation of microbicidal activity. J Immunol. 1987 Aug 15;139(4):1342–1347. [PubMed] [Google Scholar]
- Whitham S. E., Murphy G., Angel P., Rahmsdorf H. J., Smith B. J., Lyons A., Harris T. J., Reynolds J. J., Herrlich P., Docherty A. J. Comparison of human stromelysin and collagenase by cloning and sequence analysis. Biochem J. 1986 Dec 15;240(3):913–916. doi: 10.1042/bj2400913. [DOI] [PMC free article] [PubMed] [Google Scholar]