SLPI

{{Short description|Protein-coding gene in the species Homo sapiens}}

Antileukoproteinase, also known as secretory leukocyte protease inhibitor (SLPI), is an enzyme that in humans is encoded by the SLPI gene.{{cite journal | vauthors = Stetler G, Brewer MT, Thompson RC | title = Isolation and sequence of a human gene encoding a potent inhibitor of leukocyte proteases | journal = Nucleic Acids Research | volume = 14 | issue = 20 | pages = 7883–96 | date = Oct 1986 | pmid = 3640338 | pmc = 311822 | doi = 10.1093/nar/14.20.7883 }}{{cite journal | vauthors = Clauss A, Lilja H, Lundwall A | title = A locus on human chromosome 20 contains several genes expressing protease inhibitor domains with homology to whey acidic protein | journal = The Biochemical Journal | volume = 368 | issue = Pt 1 | pages = 233–42 | date = Nov 2002 | pmid = 12206714 | pmc = 1222987 | doi = 10.1042/BJ20020869 }}{{cite web | title = Entrez Gene: SLPI secretory leukocyte peptidase inhibitor| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6590}} SLPI is a highly cationic single-chain protein with eight intramolecular disulfide bonds. It is found in large quantities in bronchial, cervical, and nasal mucosa, saliva, and seminal fluids. SLPI inhibits human leukocyte elastase, human cathepsin G, human trypsin, neutrophil elastase, and mast cell chymase. X-ray crystallography has shown that SLPI has two homologous domains of 53 and 54 amino acids, one of which exhibits anti-protease activity (C-terminal domain). The other domain (N-terminal domain) is not known to have any function.

Function

This gene encodes a secreted inhibitor which protects epithelial tissues from serine proteases. It is found in various secretions including seminal plasma, cervical mucus, and bronchial secretions, and has affinity for trypsin, leukocyte elastase, and cathepsin G. Its inhibitory effect contributes to the immune response by protecting epithelial surfaces from attack by endogenous proteolytic enzymes; the protein is also thought to have broad-spectrum antibiotic activity.

Clinical significance

The gene for SLPI is expressed by cells at many mucosal surfaces located in the tissues of the lungs, cervix, seminal vesicles, and parotid ducts. SLPI is also one of the dominantly present proteins in nasal epithelial lining fluid and other nasal secretions. Tissue SLPI expression reveals a clear compartmentalization, being highest in the endocervix and lowest in the endometrium of postmenopausal women. Hormonal treatment differentially modulates tissue SLPI expression along the reproductive tract.{{cite journal | vauthors = Kumar R, Vicari M, Gori I, Achtari C, Fiche M, Surbeck I, Damnon F, Canny GO | title = Compartmentalized secretory leukocyte protease inhibitor expression and hormone responses along the reproductive tract of postmenopausal women. | journal = J Reprod Immunol | volume = 92 | issue = 1–2 | pages = 88–96 | date = September 2011 | pmid = 21940052 | doi =10.1016/j.jri.2011.06.103}} Many diseases, such as emphysema, cystic fibrosis, and idiopathic pulmonary fibrosis, are characterized by increased levels of neutrophil elastase. SLPI is one of the major defenses against the destruction of pulmonary tissues and epithelial tissues by neutrophil elastase. SLPI is considered to be the predominant elastase inhibitor in secretions, while α1-antitrypsin is the predominant elastase inhibitor in tissues. Several diseases, including those listed, are actually the result of SLPI and α1-antitrypsin defenses being overwhelmed by neutrophil elastase. It has been suggested that recombinant human SLPI be administered to treat symptoms of cystic fibrosis, genetic emphysema, and asthma. In addition, SLPI has occasionally been monitored in an effort to coordinate its levels with different pathological conditions. Increased levels of SLPI in nasal secretions and bronchoalveolar fluids may be denotive of inflammatory lung conditions or allergic reactions, and increased levels of SLPI in plasma may be indicative of pneumonia.{{cite journal | vauthors = McNeely TB, Dealy M, Dripps DJ, Orenstein JM, Eisenberg SP, Wahl SM | title = Secretory leukocyte protease inhibitor: a human saliva protein exhibiting anti-human immunodeficiency virus 1 activity in vitro | journal = The Journal of Clinical Investigation | volume = 96 | issue = 1 | pages = 456–64 | date = Jul 1995 | pmid = 7615818 | pmc = 185219 | doi = 10.1172/JCI118056 }}

Increased levels of SLPI in saliva and plasma may also be an indicator of HIV infection. This is evident due to the virtual nonexistence of HIV transmission through oral-to-oral contact. This antiviral activity is due to the interference of SLPI in events that are mediated by protease, such as entry into the host cell and replication of viral genetic material. Studies have shown that decreasing levels of SLPI in saliva also decreases its anti-HIV activity.{{cite journal | vauthors = Nagashunmugam T, Malamud D, Davis C, Abrams WR, Friedman HM | title = Human submandibular saliva inhibits human immunodeficiency virus type 1 infection by displacing envelope glycoprotein gp120 from the virus | journal = The Journal of Infectious Diseases | volume = 178 | issue = 6 | pages = 1635–41 | date = Dec 1998 | pmid = 9815215 | doi=10.1086/314511| doi-access = free }}{{cite journal | vauthors = Shugars DC, Wahl SM | title = The role of the oral environment in HIV-1 transmission | journal = Journal of the American Dental Association | volume = 129 | issue = 7 | pages = 851–8 | date = Jul 1998 | pmid = 9685760 | doi=10.14219/jada.archive.1998.0349}}{{cite journal | vauthors = Malamud D, Friedman HM | title = HIV in the oral cavity: virus, viral inhibitory activity, and antiviral antibodies: a review | journal = Critical Reviews in Oral Biology and Medicine | volume = 4 | issue = 3–4 | pages = 461–6 | date = 1993-01-01 | doi = 10.1177/10454411930040032901 | pmid = 8373998 }} What makes SLPI such a topic of interest is that it exhibits anti-HIV properties in physiological conditions, rather than artificial ones.

Furthermore, it has been shown that there is an inverse correlation between the levels of SLPI and high-risk Human Papillomavirus (HPV) infection, demonstrating that high levels of SLPI confer protection against HPV infection.{{cite journal | vauthors = Hoffmann M, Quabius ES, Tribius S, Hebebrand L, Görögh T, Halec G, Kahn T, Hedderich J, Röcken C, Haag J, Waterboer T, Schmitt M, Giuliano AR, Kast WM | title = Human papillomavirus infection in head and neck cancer: the role of the secretory leukocyte protease inhibitor | journal = Oncology Reports | volume = 29 | issue = 5 | pages = 1962–8 | date = May 2013 | pmid = 23467841 | pmc = 3658815 | doi = 10.3892/or.2013.2327 }}{{cite journal | vauthors = Pierce Campbell CM, Guan W, Sprung R, Koomen JM, O'Keefe MT, Ingles DJ, Abrahamsen M, Giuliano AR | title = Quantification of secretory leukocyte protease inhibitor (SLPI) in oral gargle specimens collected using mouthwash | journal = Journal of Immunological Methods | volume = 400–401 | pages = 117–21 | date = Dec 2013 | pmid = 24140751 | pmc = 3990009 | doi = 10.1016/j.jim.2013.10.005 }}{{cite journal | vauthors = Quabius ES, Möller P, Haag J, Pfannenschmidt S, Hedderich J, Görögh T, Röcken C, Hoffmann M | title = The role of the antileukoprotease SLPI in smoking-induced human papillomavirus-independent head and neck squamous cell carcinomas | journal = International Journal of Cancer | volume = 134 | issue = 6 | pages = 1323–34 | date = Mar 2014 | pmid = 23996702 | doi = 10.1002/ijc.28462 | s2cid = 5116569 | doi-access = free }}

Interactions

SLPI has been shown to interact with PLSCR1 and PLSCR4 on the plasma membrane of T-cells, specifically in the proximity of CD4.{{cite journal | vauthors = Tseng CC, Tseng CP | title = Identification of a novel secretory leukocyte protease inhibitor-binding protein involved in membrane phospholipid movement | journal = FEBS Letters | volume = 475 | issue = 3 | pages = 232–6 | date = Jun 2000 | pmid = 10869562 | doi = 10.1016/s0014-5793(00)01700-2 | s2cid = 35688498 | doi-access = }}{{cite journal | vauthors = Py B, Basmaciogullari S, Bouchet J, Zarka M, Moura IC, Benhamou M, Monteiro RC, Hocini H, Madrid R, Benichou S | title = The phospholipid scramblases 1 and 4 are cellular receptors for the secretory leukocyte protease inhibitor and interact with CD4 at the plasma membrane | journal = PLOS ONE | volume = 4 | issue = 3 | pages = e5006 | date = 2009-01-01 | pmid = 19333378 | pmc = 2659420 | doi = 10.1371/journal.pone.0005006 | bibcode = 2009PLoSO...4.5006P | doi-access = free }} This interaction is hypothesized to be one of the ways SLPI inhibits HIV infection.

Additionally, it has been shown that SLPI is able to bind the Annexin A2/S100A10 heterotetramer (A2t), a co-factor HIV infection, on the surface of macrophages.{{cite journal | vauthors = Ma G, Greenwell-Wild T, Lei K, Jin W, Swisher J, Hardegen N, Wild CT, Wahl SM | title = Secretory leukocyte protease inhibitor binds to annexin II, a cofactor for macrophage HIV-1 infection | journal = The Journal of Experimental Medicine | volume = 200 | issue = 10 | pages = 1337–46 | date = Nov 2004 | pmid = 15545357 | pmc = 2211913 | doi = 10.1084/jem.20041115 }} This interaction with A2t has also been shown to block HPV uptake and infection of epithelial cells.{{cite journal | vauthors = Woodham AW, Da Silva DM, Skeate JG, Raff AB, Ambroso MR, Brand HE, Isas JM, Langen R, Kast WM | title = The S100A10 subunit of the annexin A2 heterotetramer facilitates L2-mediated human papillomavirus infection | journal = PLOS ONE | volume = 7 | issue = 8 | pages = e43519 | date = 2012-01-01 | pmid = 22927980 | pmc = 3425544 | doi = 10.1371/journal.pone.0043519 | bibcode = 2012PLoSO...743519W | doi-access = free }}

SLPI

Function

Clinical significance

Interactions

References

Further reading