Alternative titles; symbols
HGNC Approved Gene Symbol: SLPI
Cytogenetic location: 20q13.12 Genomic coordinates (GRCh38) : 20:45,252,239-45,254,564 (from NCBI)
Human mucous fluids such as seminal plasma, cervical mucus, bronchial and nasal secretions, and tears contain acid-stable proteinase inhibitors with strong affinity for trypsin and chymotrypsin as well as for neutrophil lysosomal elastase and cathepsin G. The antileukoprotease from human seminal plasma HUSI-I (human seminal plasma inhibitor-I) and the inhibitor found in mucous secretions from the cervix, although isolated from different tissues, seem to be identical proteins (summary by Seemuller et al., 1986).
Heinzel et al. (1986) isolated cDNA clones for the human antileukoprotease HUSI-I from a library containing cDNA inserts made from human cervix. By screening with a mixture of over 16 different oligodeoxyribonucleotides which correspond to amino acids 79-84 and with one 20mer oligodeoxyribonucleotide corresponding to amino acids 19-26, they isolated 2 overlapping cDNA clones containing the entire coding sequence and part of the 5-prime and 3-prime untranslated regions. Seemuller et al. (1986) demonstrated structural homology to whey proteins of rat and mouse.
Thompson and Ohlsson (1986) purified from human parotid secretions a potent inhibitor of human leukocyte elastase and cathepsin G, as well as of human trypsin, and reported the complete amino acid sequence. Stetler et al. (1986) isolated the human gene encoding secretory leukocyte protease inhibitor. The protein appears to contain 2 functional domains, one having a trypsin inhibitory site and the other an elastase inhibitory site. The 2-domain structure of the protein is reflected in the organization of the gene, with each domain represented by a separate exon. SLPI is an acid-stable polypeptide of molecular mass 12 kD found also in bronchial mucus, cervical mucus, and seminal plasma.
Increased leukocyte elastase (130130) activity in mice lacking Slpi leads to impaired wound healing due to enhanced activity of transforming growth factor-beta (190180) and perhaps additional mechanisms (Ashcroft et al., 2000). Proepithelin (PEPI; 138945), also known as progranulin, an epithelial growth factor, can be converted to epithelins (EPIs) in vivo. Zhu et al. (2002) found that PEPI and EPIs exert opposing activities. EPIs inhibited the growth of epithelial cells but induced them to secrete the neutrophil attractant interleukin-8 (IL8; 146930), while PEPI blocked neutrophil activation by tumor necrosis factor (TNF; 191160), preventing release of oxidants and proteases. SLPI and PEPI formed complexes, preventing elastase from converting PEPI to EPIs. Supplying PEPI corrected the wound-healing defect in Slpi null mice. The authors concluded that SLPI/elastase act via PEPI/EPIs to operate a switch at the interface between innate immunity and wound healing.
Protease inhibitors have generally been considered to counteract tumor progression and metastasis. However, expression of serine protease inhibitors (SPIs) in tumors is often associated with poor prognosis of cancer patients. Indeed, SPIs may even promote malignancy of cancer cells. To isolate cancer-promoting genes, Devoogdt et al. (2003) used the suppression subtractive hybridization method to low-malignant versus high-malignant lung carcinoma cells. This resulted in the identification of SLPI as one of the genes whose expression was greater in highly malignant cells than in cells of low malignant potential. By stable transfection of the low malignancy cells with mouse or human SLPI, they demonstrated that elevated levels of SLPI expression increased both the tumorigenicity and lung-colonizing potential of the cancer cells. Furthermore, they demonstrated that this function of SLPI depended on its protease inhibitory capacity.
Using a yeast 2-hybrid screen, Schulze et al. (2004) found that the C terminus of mouse Tubb1 (602901), a major component of the platelet microtubule marginal band, interacted with Slpi. Slpi was expressed in megakaryocytes and platelets in a punctate cytoplasmic distribution, and it colocalized with Tubb1 along the marginal band. In Tubb1 -/- platelets, association of Slpi with microtubules was lost and the capacity of Slpi to inhibit neutrophil elastase was reduced. Slpi was released upon platelet activation, which also decreased the association of Slpi with Tubb1 and with the marginal band. Schulze et al. (2004) concluded that the association of SLPI with microtubules is TUBB1 dependent and that its punctate distribution within platelets is TUBB1 independent.
Using healthy human skin fragments obtained as surgical residua, Sorensen et al. (2006) demonstrated that sterile wounding of human skin induces epidermal expression of the antimicrobial polypeptides beta-defensin-103 (DEFB103; 606611), lipocalin-2 (LCN2; 600181), and SLPI through activation of EGFR (131550) by heparin-binding EGF (HBEGF; 126150).
Wagenblast et al. (2015) developed a polyclonal mouse model of breast tumor heterogeneity and showed that distinct clones within a mixed population display specialization, for example, by dominating the primary tumor, contributing to metastatic populations, or showing tropism for entering the lymphatic or vasculature systems. The authors correlated these stable properties to distinct gene expression profiles. Those clones that efficiently enter the vasculature express 2 secreted proteins, SERPINE2 (177010) and SLPI, which are necessary and sufficient to program these cells for vascular mimicry. The data indicated that these proteins not only drive the formation of extravascular networks but also ensure their perfusion by acting as anticoagulants. Wagenblast et al. (2015) proposed that vascular mimicry drives the ability of some breast tumor cells to contribute to distant metastases while simultaneously satisfying a critical need of the primary tumor to be fed by the vasculature. Enforced expression of SERPINE2 and SLPI in human breast cancer cell lines also programmed them for vascular mimicry, and SERPINE2 and SLPI were overexpressed preferentially in human patients who had lung-metastatic relapse. Wagenblast et al. (2015) proposed that these 2 secreted proteins, and the phenotype they promote, may be broadly relevant as drivers of metastatic progression in human cancer.
Stetler et al. (1986) determined that the SLPI gene has 2 exons. The intervening sequence separating the 2 exons is flanked by 11 bp direct repeats, suggesting that this intron may have been generated by a transposition-type event.
Schulze et al. (2004) stated that the mouse Slpi gene maps to chromosome 2.
Nakamura et al. (2003) generated Slpi -/- mice and analyzed their response to shock induced by lipopolysaccharide (LPS). Slpi -/- mice had a higher mortality from endotoxin shock than wildtype mice. Macrophages from Slpi -/- mice produced higher levels of Il6 (147620) and Hmg1 (HMGB1; 163905) and showed greater Nfkb (164011) activation after LPS treatment than wildtype macrophages. LPS treatment also induced Slpi -/- B cells to produce more IgM and proliferate at higher levels. Nakamura et al. (2003) proposed that SLPI attenuates excessive inflammatory responses.
Ashcroft, G. S., Lei, K., Jin, W., Longenecker, G., Kulkarni, A. B., Greenwell-Wild, T., Hale-Donze, H., McGrady, G., Song, X.-Y., Wahl, S. M. Secretory leukocyte protease inhibitor mediates non-redundant functions necessary for normal wound healing. Nature Med. 6: 1147-1153, 2000. [PubMed: 11017147] [Full Text: https://doi.org/10.1038/80489]
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. Nat. Acad. Sci. 100: 5778-5782, 2003. [PubMed: 12732717] [Full Text: https://doi.org/10.1073/pnas.1037154100]
Heinzel, R., Appelhans, H., Gassen, G., Seemuller, U., Machleidt, W., Fritz, H., Steffens, G. Molecular cloning and expression of cDNA for human antileukoprotease from cervix uterus. Europ. J. Biochem. 160: 61-67, 1986. [PubMed: 3533531] [Full Text: https://doi.org/10.1111/j.1432-1033.1986.tb09940.x]
Nakamura, A., Mori, Y., Hagiwara, K., Suzuki, T., Sakakibara, T., Kikuchi, T., Igarashi, T., Ebina, M., Abe, T., Miyazaki, J., Takai, T., Nukiwa, T. Increased susceptibility to LPS-induced endotoxin shock in secretory leukoprotease inhibitor (SLPI)-deficient mice. J. Exp. Med. 197: 669-674, 2003. [PubMed: 12615907] [Full Text: https://doi.org/10.1084/jem.20021824]
Schulze, H., Korpal, M., Bergmeier, W., Italiano, J. E., Jr., Wahl, S. M., Shivdasani, R. A. Interactions between the megakaryocyte/platelet-specific beta-1 tubulin and the secretory leukocyte protease inhibitor SLPI suggest a role for regulated proteolysis in platelet functions. Blood 104: 3949-3957, 2004. [PubMed: 15315966] [Full Text: https://doi.org/10.1182/blood-2004-03-1179]
Seemuller, 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. 199: 43-48, 1986. [PubMed: 3485543] [Full Text: https://doi.org/10.1016/0014-5793(86)81220-0]
Sorensen, O. E., Thapa, D. R., Roupe, K. M., Valore, E. V., Sjobring, U., Roberts, A. A., Schmidtchen, A., Ganz, T. Injury-induced innate immune response in human skin mediated by transactivation of the epidermal growth factor receptor. J. Clin. Invest. 116: 1878-1885, 2006. [PubMed: 16778986] [Full Text: https://doi.org/10.1172/JCI28422]
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. 14: 7883-7896, 1986. [PubMed: 3640338] [Full Text: https://doi.org/10.1093/nar/14.20.7883]
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. Nat. Acad. Sci. 83: 6692-6696, 1986. [PubMed: 3462719] [Full Text: https://doi.org/10.1073/pnas.83.18.6692]
Wagenblast, E., Soto, M., Gutierrez-Angel, S., Hartl, C. A., Gable, A. L., Maceli, A. R., Erard, N., Williams, A. M., Kim, S. Y., Dickopf, S., Harrell, J. C., Smith, A. D., Perou, C. M., Wilkinson, J. E., Hannon, G. J., Knott, S. R. V. A model of breast cancer heterogeneity reveals vascular mimicry as a driver of metastasis. Nature 520: 358-362, 2015. [PubMed: 25855289] [Full Text: https://doi.org/10.1038/nature14403]
Zhu, J., Nathan, C., Jin, W., Sim, D., Ashcroft, G. S., Wahl, S. M., Lacomis, L., Erdjument-Bromage, H., Tempst, P., Wright, C. D., Ding, A. Conversion of proepithelin to epithelins: roles of SLPI and elastase in host defense and wound repair. Cell 111: 867-878, 2002. [PubMed: 12526812] [Full Text: https://doi.org/10.1016/s0092-8674(02)01141-8]