Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Secretory Leukocyte Protease Inhibitor (SLPI)

  • Sari S. HannilaEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101834


Historical Background

Secretory leukocyte protease inhibitor (SLPI) was first described by Robert Thompson and Kjell Ohlsson in a 1986 study that aimed to identify novel leukocyte protease inhibitors in human saliva (Thompson and Ohlsson 1986). In their experiments, SLPI was purified from human parotid saliva using Sephadex columns, and the protein was found to have a molecular weight of 11.7 kD. Subsequent studies determined that high levels of SLPI are also present in bronchial mucus, seminal fluid, lacrimal secretions, breast milk, and cervical mucus. The biochemical analyses conducted by Thompson and Ohlsson revealed that SLPI inhibited the activity of leukocyte (neutrophil) elastase, cathepsin G,...

This is a preview of subscription content, log in to check access.


  1. Antoniades CG, Khamri W, Abeles RD, Taams LS, Triantafyllou E, Possamai LA, Bernsmeier C, Mitry RR, O’Brien A, Gilroy D, Goldin R, Heneghan M, Heaton N, Jassem W, Bernal W, Vergani D, Ma Y, Quaglia A, Wendon J, Thursz M. Secretory leukocyte protease inhibitor: a pivotal mediator of anti-inflammatory responses in acetaminophen-induced acute liver failure. Hepatology. 2014;59:1564–76.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Ashcroft GS, Lei K, Jin W, Longenecker G, Kulkarni AB, Greenwell-Wild T, Hale-Donze H, McGrady G, Song XY, Wahl SM. Secretory leukocyte protease inhibitor mediates non-redundant functions necessary for normal wound healing. Nat Med. 2000;6:1147–53.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Cooper MD, Roberts MH, Barauskas OL, Jarvis GA. Secretory leukocyte protease inhibitor binds to Neisseria gonorrhoeae outer membrane opacity protein and is bactericidal. Am J Reprod Immunol. 2012;68:116–27.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Devoogdt N, Hassanzadeh Ghassabeh G, Zhang J, Brys L, De Baetselier P, Revets H. Secretory leukocyte protease inhibitor promotes the tumorigenic and metastatic potential of cancer cells. Proc Natl Acad Sci USA. 2003;100:5778–82.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Devoogdt N, Rasool N, Hoskins E, Simpkins F, Tchabo N, Kohn EC. Overexpression of protease inhibitor-dead secretory leukocyte protease inhibitor causes more aggressive ovarian cancer in vitro and in vivo. Cancer Sci. 2009;100:434–40.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Eisenberg SP, Hale KK, Heimdal P, Thompson RC. Location of the protease-inhibitory region of secretory leukocyte protease inhibitor. J Biol Chem. 1990;265:7976–81.PubMedPubMedCentralGoogle Scholar
  7. Foth BJ, Tsai IJ, Reid AJ, Bancroft AJ, Nichol S, Tracey A, Holroyd N, Cotton JA, Stanley EJ, Zarowiecki M, Liu JZ, Huckvale T, Cooper PJ, Grencis RK, Berriman M. Whipworm genome and dual-species transcriptome analyses provide molecular insights into an intimate host-parasite interaction. Nat Genet. 2014;46:693–700.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Ghasemlou N, Bouhy D, Yang J, López-Vales R, Haber M, Thuraisingam T, He G, Radzioch D, Ding A, David S. Beneficial effects of secretory leukocyte protease inhibitor after spinal cord injury. Brain. 2010;133:126–38.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Ghidoni R, Flocco R, Paterlini A, Glionna M, Caruana L, Tonoli E, Binetti G, Benussi L. Secretory leukocyte protease inhibitor protein regulates the penetrance of frontotemporal lobar degeneration in progranulin mutation carriers. J Alzheimers Dis. 2014;38:533–9.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Gomez SA, Argüelles CL, Guerrieri D, Tateosian NL, Amiano NO, Slimovich R, Maffia PC, Abbate E, Musella RM, Garcia VE, Chuluyan HE. Secretory leukocyte protease inhibitor: a secreted pattern recognition receptor for mycobacteria. Am J Respir Crit Care Med. 2009;179:247–53.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Grütter MG, Fendrich G, Huber R, Bode W. The 2.5 A X-ray crystal structure of the acid-stable proteinase inhibitor from human mucous secretions analysed in its complex with bovine alpha-chymotrypsin. EMBO J. 1988;7:345–51.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Hannila SS, Siddiq MM, Carmel JB, Hou J, Chaudhry N, Bradley PMJ, Hilaire M, Richman EL, Hart RP, Filbin MT. Secretory leukocyte protease inhibitor reverses inhibition by CNS myelin, promotes regeneration in the optic nerve, and suppresses expression of the TGFβ signaling protein Smad2. J Neurosci. 2013;33:5138–51.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Hiemstra PS, Maassen RJ, Stolk J, Heinzel-Wieland R, Steffens GJ, Dijkman JH. Antibacterial activity of antileukoprotease. Infect Immun. 1996;64:4520–4.PubMedPubMedCentralGoogle Scholar
  14. Iłżecka J, Stelmasiak Z. Increased serum levels of endogenous protectant secretory leukocyte protease inhibitor in acute ischemic stroke patients. Cerebrovasc Dis. 2002;13:38–42.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Jiménez-Vega F, Vargas-Albores F. A secretory leukocyte proteinase inhibitor (SLPI)-like protein from Litopenaeus vannamei haemocytes. Fish Shellfish Immunol. 2007;23:1119–26.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Jin FY, Nathan C, Radzioch D, Ding A. Secretory leukocyte protease inhibitor: a macrophage product induced by and antagonistic to bacterial lipopolysaccharide. Cell. 1997;88:417–26.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Kluger HM, Kluger Y, Gilmore-Hebert M, DiVito K, Chang JT, Rodov S, Mironenko O, Kacinski BM, Perkins AS, Sapi E. cDNA microarray analysis of invasive and tumorigenic phenotypes in a breast cancer model. Lab Invest. 2004;84:320–31.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Lentsch AB, Yoshidome H, Warner RL, Ward PA, Edwards MJ. Secretory leukocyte protease inhibitor in mice regulates local and remote organ inflammatory injury induced by hepatic ischemia/reperfusion. Gastroenterology. 1999a;117:953–61.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Lentsch AB, Jordan JA, Czermak BJ, Diehl KM, Younkin EM, Sarma V, Ward PA. Inhibition of NF-kappaB activation and augmentation of IkappaBbeta by secretory leukocyte protease inhibitor during lung inflammation. Am J Pathol. 1999b;154:239–47.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Lilo E, Wald-Altman S, Solmesky LJ, Ben Yaakov K, Gershoni-Emek N, Bulvik S, Kassis I, Karussis D, Perlson E, Weil M. Characterization of human sporadic ALS biomarkers in the familial ALS transgenic mSOD1(G93A) mouse model. Hum Mol Genet. 2013;22:4720–5.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Ma G, Greenwell-Wild T, Lei K, Jin W, Swisher J, Hardegen N, Wild CT, Wahl SM. Secretory leukocyte protease inhibitor binds to annexin II, a cofactor for macrophage HIV-1 infection. J Exp Med. 2004;200:1337–46.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 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;96:456–64.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Miller KW, Evans RJ, Eisenberg SP, Thompson RC. Secretory leukocyte protease inhibitor binding to mRNA and DNA as a possible cause of toxicity to Escherichia coli. J Bacteriol. 1989;171:2166–72.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Mueller AM, Pedré X, Stempfl T, Kleiter I, Couillard-Despres S, Aigner L, Giegerich G, Steinbrecher A. Novel role for SLPI in MOG-induced EAE revealed by spinal cord expression analysis. J Neuroinflammation. 2008;5:20.PubMedPubMedCentralCrossRefGoogle Scholar
  25. Py B, Basmaciogullari S, Bouchet J, Zarka M, Moura IC, Benhamou M, Monteiro RC, Hocini H, Madrid R, Benichou S. The phospholipid scramblases 1 and 4 are cellular receptors for the secretory leukocyte protease inhibitor and interact with CD4 at the plasma membrane. PLoS One. 2009;4:e5006.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Schneeberger S, Hautz T, Wahl SM, Brandacher G, Sucher R, Steinmassl O, Steinmassl P, Wright CD, Obrist P, Werner ER, Mark W, Troppmair J, Margreiter R, Amberger A. The effect of secretory leukocyte protease inhibitor (SLPI) on ischemia/reperfusion injury in cardiac transplantation. Am J Transplant. 2008;8:773–82.PubMedPubMedCentralCrossRefGoogle Scholar
  27. Simpkins FA, Devoogdt NM, Rasool N, Tchabo NE, Alejandro EU, Kamrava MM, Kohn EC. The alarm anti-protease, secretory leukocyte protease inhibitor, is a proliferation and survival factor for ovarian cancer cells. Carcinogenesis. 2008;29:466–72.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Si-Tahar M, Merlin D, Sitaraman S, Madara JL. Constitutive and regulated secretion of secretory leukocyte proteinase inhibitor by human intestinal epithelial cells. Gastroenterology. 2000;118:1061–71.PubMedPubMedCentralCrossRefGoogle Scholar
  29. Sugino T, Yamaguchi T, Ogura G, Kusakabe T, Goodison S, Homma Y, Suzuki T. The secretory leukocyte protease inhibitor (SLPI) suppresses cancer cell invasion but promotes blood-borne metastasis via an invasion-independent pathway. J Pathol. 2007;212:152–60.PubMedPubMedCentralCrossRefGoogle Scholar
  30. Taggart CC, Greene CM, McElvaney NG, O’Neill S. Secretory leucoprotease inhibitor prevents lipopolysaccharide-induced IkappaBalpha degradation without affecting phosphorylation or ubiquitination. J Biol Chem. 2002;277:33648–53.PubMedPubMedCentralCrossRefGoogle Scholar
  31. Taggart CC, Cryan SA, Weldon S, Gibbons A, Greene CM, Kelly E, Low TB, O’Neill SJ, McElvaney NG. Secretory leucoprotease inhibitor binds to NF-kappaB binding sites in monocytes and inhibits p65 binding. J Exp Med. 2005;202:1659–68.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 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;83:6692–6.PubMedPubMedCentralCrossRefGoogle Scholar
  33. Wagenblast E, Soto M, Gutiérrez-Ángel S, Hartl CA, Gable AL, Maceli AR, Erard N, Williams AM, Kim SY, Dickopf S, Harrell JC, Smith AD, Perou CM, Wilkinson JE, Hannon GJ, Knott SR. A model of breast cancer heterogeneity reveals vascular mimicry as a driver of metastasis. Nature. 2015;520:358–62.PubMedPubMedCentralCrossRefGoogle Scholar
  34. Wang X, Li X, Xu L, Zhan Y, Yaish-Ohad S, Erhardt JA, Barone FC, Feuerstein GZ. Up-regulation of secretory leukocyte protease inhibitor (SLPI) in the brain after ischemic stroke: adenoviral expression of SLPI protects brain from ischemic injury. Mol Pharmacol. 2003;64:833–40.PubMedPubMedCentralCrossRefGoogle Scholar
  35. Zheng D, Gui B, Gray KP, Tinay I, Rafiei S, Huang Q, Sweeney CJ, Kibel AS, Jia L. Secretory leukocyte protease inhibitor is a survival and proliferation factor for castration-resistant prostate cancer. Oncogene. 2016;35:4807–15.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.University of ManitobaWinnipegCanada