Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Secretory Leukocyte Protease Inhibitor (SLPI)

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, trypsin, and chymotrypsin. These findings established SLPI as a potent and broad-spectrum inhibitor of serine proteases, and it is functionally related to other antiproteases such as α1-antitrypsin and elafin. Since its discovery, SLPI has been characterized as an alarm antiprotease that protects the oral, bronchial, and urogenital mucosae from inflammation and proteolytic damage.

Protein Structure

Human SLPI is synthesized as a single polypeptide chain measuring 132 amino acids in length. A N-terminal 25-amino acid signal peptide is cleaved prior to secretion of the protein, resulting in a mature, non-glycosylated protein composed of 107 amino acids. One of the most unique aspects of SLPI is its amino acid composition, as four amino acids account for nearly 50% of the polypeptide sequence. SLPI contains 16 cysteine residues (15%), extremely high levels of proline (13 residues – 12%), and a high percentage of lysine and arginine (16%) that contributes to the cationic nature of the protein (Grütter et al. 1988). The tertiary structure of SLPI resembles that of a boomerang, with a short linking region joining the N-terminal domain to the C-terminal domain (Grütter et al. 1988). These domains have a high degree of homology and stability, with each domain displaying a planar structure that consists of a β-hairpin loop surrounded by a wider outer loop (Grütter et al. 1988). The domain cores are notable for their lack of hydrophobicity. The polypeptide chains of each domain are covalently linked by four highly conserved disulfide bonds, forming a structure known as a whey acidic protein four-disulfide core (WFDC) motif. SLPI is therefore commonly classified as a member of the WFDC family of proteins and is occasionally referred to as WFDC4. The WFDC protein family has over 20 members, including anosmin-1 (WFDC19), epididymal peptidase inhibitor (WFDC7), peptidase inhibitor 3 (WFDC14), and semenogelins-1 and semenogelins-2. The majority of these proteins are encoded at a single locus (WFDC locus) on chromosome 20 in humans, but the genes encoding other WFDC-containing proteins such as WAP, follistatin/Kazal, immunoglobulin, Kunitz and netrin domain containing 1 (WFIKKN1) are found at other sites within the genome. Due to the highly conserved nature of WFDC domains, there is a high degree of sequence identity in mammalian SLPI. Human SLPI shares 60% amino acid sequence identity with mouse SLPI and 63% identity with rat SLPI (Wang et al. 2003). SLPI-like proteins have also been identified in invertebrates such as the whiteleg shrimp (Litopenaeus vannamei; Jiménez-Vega and Vargas-Albores 2007) and human whipworm (Trichuris trichiura; Foth et al. 2014).

X-ray crystallography has revealed that SLPI interacts with proteases via its C-terminal domain, and the eight amino acids responsible for this interaction are found in the outer loop between Thr67 and Leu74 (Grütter et al. 1988; Fig. 1). Two additional residues found in the inner loop, Met96 and Cys97, play a minor role in enzyme binding. SLPI’s mechanism of protease inhibition is similar to that of inhibitors that contain Kunitz and/or Kazal domains, as the outer loop of the C-terminal domain binds to the catalytic site of the enzyme and blocks its interaction with potential substrates. Based on the crystal structure of SLPI interacting with chymotrypsin, it was postulated that Leu72 was the residue that occupied the S1 pocket of the protease, and this was tested in a study in which numerous SLPI variants containing single amino acid substitutions at position 72 were prepared (Eisenberg et al. 1990). In variants where Leu72 was substituted with glycine, SLPI was unable to inhibit chymotrypsin, elastase, and trypsin, whereas glycine substitutions at Met73 or Leu 74 had little effect on the function of the protein. It was determined that the loss of function observed with SLPI-Gly72 was not due to conformational changes in the protein, and it was therefore concluded that the protease inhibition site for SLPI is located at Leu72 (Fig. 1).
Secretory Leukocyte Protease Inhibitor (SLPI), Fig. 1

Protein structures depicting the C-terminal domain of human SLPI (red) interacting with human neutrophil elastase (blue). The outer loop of SLPI’s C-terminal domain (aa. 67–74) binds to the catalytic site of the enzyme, and the side chain of Leu72, the residue responsible for inhibiting protease function, is highlighted in green. The original crystal structure of the SLPI-elastase complex can be accessed in the Protein Data Bank using code 2Z7F (Koizumi M, Fujino A, Fukushima K, Kamimura T, Takimoto-Kamimura M. Complex of human neutrophil elastase with 1/2SLPI. J Synchrotron Radiat. 2008;15:308–11.). Molecular graphics were produced with the UCSF Chimera package, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by NIGMS P41-GM103311; Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE. UCSF Chimera – a visualization system for exploratory research and analysis. J Comput Chem. 2004;25:1605–12)

SLPI and Microorganisms

Soon after its antiprotease activity was characterized, SLPI was shown to have antimicrobial effects as well (Fig. 2). In Escherichia coli genetically modified to express SLPI, the growth of the bacteria was attenuated, and there were significant reductions in both RNA and protein synthesis (Miller et al. 1989). The same study demonstrated that SLPI could bind directly to DNA and RNA and inhibit translation by 75% in a cell-free system. The reduction in bacterial growth was attributed to this decrease in protein expression. Since the publication of these findings, numerous studies have demonstrated that SLPI can inhibit the growth and survival of several other bacterial species. Addition of exogenous SLPI to cultures of E. coli resulted in not only growth arrest but also death of the bacteria, as no culturable bacteria were retrieved following treatment with high concentrations of SLPI (Hiemstra et al. 1996). Similar results were obtained for Staphylococcus aureus, which indicated that SLPI was bactericidal for both strains (Hiemstra et al. 1996). Interestingly, when tested individually, the N-terminal domain of SLPI was found to have significantly more antibacterial activity than the C-terminal domain, which suggested that the ability of SLPI to kill bacteria was unrelated to its antiprotease function (Hiemstra et al. 1996). More recently, microbiologists have shown that SLPI is bactericidal for three obligate human pathogens: Salmonella typhimurium, Mycobacterium tuberculosis, and Neisseria gonorrhoeae (Si-Tahar et al. 2000; Gomez et al. 2009; Cooper et al. 2012). In the case of M. tuberculosis, it was found that SLPI bound to mannan-capped lipoarabinomannans and phosphatidylinositol mannoside on the surface of the bacterium, facilitating phagocytosis and killing of the bacteria. Intranasal administration of SLPI also reduced the number of viable bacteria in the lungs of mice infected with M. tuberculosis, providing the first evidence that SLPI can counter bacterial infection in vivo.
Secretory Leukocyte Protease Inhibitor (SLPI), Fig. 2

Schematic representation of SLPI’s bactericidal effects on Mycobacterium tuberculosis, Escherichia coli, Salmonella typhimurium, and Neisseria gonorrhoeae

SLPI also displays antiviral properties, and perhaps its best-known function is its ability to inhibit infection of monocytes and macrophages by human immunodeficiency virus (HIV). It had been known since the mid-1980s that oral transmission of HIV was extremely low and that human saliva possessed significant anti-HIV activity that was not present in other bodily fluids such as plasma, urine, synovial fluid, and cerebrospinal fluid (McNeely et al. 1995). This prompted several studies aimed at identifying the factors in human saliva that were responsible for this effect. In an in vitro study that examined HIV infection of monocytes and T lymphocytes, SLPI was the only salivary protein that displayed significant anti-HIV activity at physiological concentrations (McNeely et al. 1995). Other salivary proteins such as statherin, cystatin, lactoferrin, and lysozyme failed to inhibit infection or only inhibited infection at nonphysiological concentrations. Depletion of SLPI from saliva led to a 50% reduction in its ability to prevent HIV infection, indicating that SLPI is primarily responsible for the anti-HIV activity in saliva.

SLPI does not directly affect the survival or function of HIV itself, but rather mediates its effects by blocking the interaction of the virus with proteins on the surfaces of target cells. It was first shown that SLPI can bind to annexin II on macrophages and that the presence of SLPI disrupts the interaction of annexin II with the human phosphatidylserine that is acquired by HIV from host cells and displayed on the outer coat of the virus (Ma et al. 2004). It was proposed that disrupting the interaction with annexin II does not prevent binding of HIV to the target cell, but rather inhibits postbinding and the pre-reverse transcription phase of the viral life cycle. In 2009, phospholipid scramblase 1 (PLSCR1) was identified as a receptor for SLPI on the surfaces of T lymphocytes (Py et al. 2009). The cytoplasmic domain of PLSCR1 interacts with CD4, the receptor that binds HIV on T lymphocytes, and it has been suggested that the interaction between PLSCR1 and CD4 facilitates fusion of HIV with the plasma membrane of the host cell. It was shown that SLPI can disrupt this interaction by competitively binding to the same site on PLSCR1, and it was therefore proposed that SLPI may inhibit HIV infection of T lymphocytes by modulating CD4 function. To date, there has been no further insight into the mechanism that underlies SLPI’s ability to inhibit HIV infection, but this remains an active area of study within the field.

SLPI and Inflammation

SLPI plays an important role in suppressing the inflammatory responses that occur in response to tissue injury. In mice with a germ line null mutation of SLPI (Slpi –/– ), cutaneous wound healing was severely impaired, and there was increased inflammation at the site of injury that was associated with extensive infiltration of neutrophils and macrophages (Ashcroft et al. 2000). Elastase activity was also elevated within the lesion site, and this led to the assertion that the collagen matrix was being digested by elastase in the absence of SLPI’s antiprotease activity, preventing closure of the wound. It now appears, however, that inhibition of proteases is only a small component of SLPI’s anti-inflammatory function, as numerous studies have demonstrated that SLPI can downregulate the expression of pro-inflammatory cytokines. The first evidence of this was obtained in a study showing that SLPI can inhibit the expression of tumor necrosis factor α (TNFα) in mouse macrophage cell lines treated with lipopolysaccharide (LPS; Jin et al. 1997). Exposure to LPS in vivo also induced SLPI expression in mouse primary macrophages and polymorphonuclear leukocytes, as well as the lung and spleen, which suggested that SLPI is widely upregulated in response to a pro-inflammatory stimulus. Similar results have been obtained in studies of lung and liver injury. In mice that underwent hepatic ischemia/reperfusion injury, the lung and liver displayed significant cellular injury and infiltration of neutrophils as indicated by increased levels of serum alanine aminotransferase and tissue myeloperoxidase, respectively (Lentsch et al. 1999a). Significant increases in serum TNFα and macrophage inflammatory protein-2 (MIP-2) were also observed in these animals, along with induction of SLPI mRNA and protein expression in the liver. When SLPI was administered intravenously prior to the induction of ischemia and at the start of reperfusion, levels of TNFα, MIP-2, alanine aminotransferase, and myeloperoxidase were all significantly reduced in both lung and liver. SLPI can also regulate the conversion of transforming growth factor β (TGFβ) to its active form. Elevated levels of active TGFβ were observed in the epidermis of Slpi –/– mice 2 days after cutaneous injury, and the application of either SLPI or anti-TGFβ to the injury site decreased TGFβ levels, reduced inflammation, and reversed the impaired wound healing response normally seen in these animals (Ashcroft et al. 2000). These observations suggested that TGFβ acted as a chemoattractive factor for infiltrating leukocytes, leading to increased inflammation within the lesion site and that SLPI inhibits this response.

A common finding in many of the studies described above was that SLPI not only reduced pro-inflammatory cytokine levels but also inhibited the activity of the transcription factor nuclear factor-κB (NF-κB) activity (Jin et al. 1997). Initially, it was believed that SLPI mediated this effect by blocking proteasomal degradation of IκBα and IκBβ, which bind to NF-κB and prevent its translocation to the nucleus. This was supported by the observation that IκBα and IκBβ levels were increased following administration of SLPI in a model of pulmonary inflammation in rats (Lentsch et al. 1999b) and in the U937 monocyte cell line (Taggart et al. 2002). Further investigation of this phenomenon, however, has revealed that the SLPI-mediated regulation of NF-κB and pro-inflammatory gene expression is far more complex. A landmark study by Taggart et al. (2005) reported that SLPI can cross the plasma membrane and localize to the nuclei of monocytes, where it binds directly to DNA. Remarkably, this was not a random interaction driven by SLPI’s strong positive charge. Rather, SLPI bound specifically to AP-1 and NF-κB binding sites within the genome and blocked binding of the p65 subunit of NF-κB to these sites, leading to reduced transcription (Fig. 3). Chromatin immunoprecipitation experiments then demonstrated that SLPI can bind to the promoter sequences for TNFα and interleukin-8 (IL-8), but not the anti-inflammatory cytokine interleukin-10 (IL-10), which suggested that SLPI inhibits the expression of pro-inflammatory cytokines at the transcriptional level. This was confirmed using enzyme-linked immunosorbent assays, which showed that levels of TNFα and IL-8, but not IL-10, were reduced when LPS-stimulated monocytes were treated with SLPI. The elucidation of this mechanism has sparked considerable interest in SLPI as an anti-inflammatory agent, and in the last decade, researchers have begun to explore its potential clinical benefits, including as an additive in the preservation solutions used to reduce ischemia-reperfusion injury in donor hearts awaiting transplantation (Schneeberger et al. 2008) and as an anti-inflammatory factor in acetaminophen-induced hepatic failure (Antoniades et al. 2014).
Secretory Leukocyte Protease Inhibitor (SLPI), Fig. 3

SLPI localizes to the nuclei of mammalian cells and binds to NF-κB-binding sites within specific promoters. This physically prevents binding of NF-κB (composed of p65/RelA and p50) to the promoter and blocks transcription of the gene

SLPI and Cancer

The role of SLPI in cancer has been widely debated. Some studies have reported that SLPI can inhibit proliferation and induce apoptosis in tumor cells, but the majority of studies in this field have identified SLPI as a factor that promotes invasion and metastasis. One piece of information that is not in question is that SLPI is highly expressed by a variety of tumor cell lines, including T98G human glioblastoma cells, Lewis lung carcinoma 3LL-S-sc cells, SKOV3 ovarian cancer cells, and GILM2 breast carcinoma cells. High levels of SLPI have also been reported in primary tumors such as colon adenoma, gastric carcinoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, and non-small cell lung carcinoma. This elevated expression has been associated with increased aggressiveness of the disease. High levels of SLPI expression led to enhanced tumorigenicity and proliferation of Lewis lung carcinoma 3LL-S-sc cells in vitro and increased the formation of lung metastases when these cells were injected in vivo (Devoogdt et al. 2003). In a study of breast cancer invasion and metastasis, HC11 mammary epithelial cells expressing the cfms proto-oncogene displayed significant increases in SLPI mRNA expression and corresponding increases in invasiveness and metastatic potential (Kluger et al. 2004). Finally, the survival, proliferation, and invasiveness of Hey-A8 ovarian cancer cells were enhanced when SLPI was overexpressed in these cells (Devoogdt et al. 2009). These responses were unchanged when the Hey-A8 cells were stably transfected to express SLPI that lacked protease inhibitor activity, which suggests that this function is not required for the ability of SLPI to enhance invasion and metastasis. Because of the strong correlation between elevated SLPI and malignancy and due to its presence in readily accessible fluids such as saliva, blood, and mucus, SLPI is being actively investigated as a potential diagnostic and prognostic biomarker for cancer.

While no definitive mechanism has been identified, new information continues to emerge regarding the signaling events and morphological changes that occur when tumor cells are exposed to SLPI. It has been reported that SLPI can induce sinusoidal angiogenesis and vascular remodeling in mice inoculated with MCH66C8 mammary tumor cells and that this promotes metastasis to the lung (Sugino et al. 2007). A 2015 study published in Nature has now provided further support for a vascular link between SLPI and metastasis (Wagenblast et al. 2015). In a mouse model of mammary carcinoma, SLPI expression was strongly correlated with metastatic progression. It was found that SLPI induced differentiation of the tumor cells into endothelial-like cells, a phenomenon known as vascular mimicry, which resulted in the formation of extravascular networks that carried blood to the tumor’s hypoxic core. SLPI also acted as an anticoagulant within these networks, which enhanced perfusion of the tumor and facilitated intravasation and metastasis of the tumor cells (Wagenblast et al. 2015). SLPI has also been shown to influence the survival and proliferation of cancer cells through regulation of the growth factor progranulin. In ovarian cancer cells, SLPI bound directly to progranulin, protecting it from degradation by elastase, and this significantly increased the survival and growth of the cells (Simpkins et al. 2008). This effect was confirmed using siRNA knockdown of SLPI, which resulted in reduced progranulin levels and increased apoptosis in the SKOV3 ovarian cancer cell line. Similar results were obtained in a recent study of castration-resistant prostate cancer (Zheng et al. 2016). Once again, SLPI expression was highly elevated in both prostate cancer cell lines and patient samples, and there was a strong correlation between SLPI-progranulin binding and the proliferation of human LNCaP prostate cancer cells. SLPI also significantly reduced TNFα-induced apoptosis in these cells, and based on the results of experiments with SLPI siRNA, the authors proposed that SLPI suppressed the expression of pro-apoptotic genes associated with the p53 pathway. These included cyclin-dependent kinase inhibitor 1A, TP53, Bcl-2-binding component 3, GADD45G, and sestrin-2. While it was not investigated in the study, it is possible that SLPI may regulate the expression of these genes by binding to their promoters and blocking transcription in a manner similar to that described for TNFα, and this would represent a new and intriguing avenue of investigation for cancer researchers.

SLPI and the Central Nervous System

Until recently, SLPI had been studied almost exclusively in the context of inflammation, infectious disease, and cancer, but researchers are now examining SLPI’s effects in the central nervous system (CNS). One of the first studies in this area reported that elevated levels of SLPI were present in human patients following ischemic stroke (Iłżecka and Stelmasiak 2002). When compared to control subjects, SLPI was significantly increased in serum samples obtained from patients at 5 and 12 days after stroke, and this elevated expression was associated with poor neurological outcomes and increased lesion size. Wang et al. (2003) then determined that SLPI mRNA expression was significantly elevated in ipsilateral cerebral cortex 12 h after a unilateral middle cerebral artery occlusion (MCAO) in rats and that this elevated expression was maintained for 5 days after the insult. Immunohistochemical staining for SLPI was present in neurons and astrocytes (but not macrophages or microglia) at 24 and 72 h after MCAO, which indicated that SLPI protein was expressed in response to ischemia. No induction of SLPI expression was observed in non-ischemic cortex or sham controls. Most importantly, rats that received intracortical injections of SLPI-expressing adenovirus 2 days prior to MCAO displayed improved neurological function and significant reductions in cortical lesion volume as measured by tetrazolium chloride staining. This suggested that SLPI is neuroprotective, and it has been proposed that SLPI is upregulated in an attempt to limit neuroinflammation and ischemic damage.

SLPI has been shown to have similar effects and patterns of expression in models of CNS injury. SLPI mRNA levels were dramatically increased 1 day after a moderate thoracic spinal cord contusion in mice and remained elevated until 7 days after injury (Ghasemlou et al. 2010). The amount of SLPI within the lesion site was also visibly higher when assessed by Western blot, reaching a maximum of 3 days after injury, and immunohistochemistry revealed that the protein was present in neurons, astrocytes, and neutrophils. To determine if SLPI could enhance functional recovery, wild-type mice underwent contusion injury and the animals then received daily intraperitoneal injections of SLPI for 7 days. When compared to mice that received saline, SLPI-treated mice showed significant improvement in locomotion over a 28-day period as measured by the Basso Mouse Scale. The spinal cords of these animals also displayed morphological changes that were indicative of neuroprotection, including increased tissue sparing and myelination, significant increases in the number of ventral horn motor neurons, and greater density of serotonergic axons caudal to the lesion site. In a subsequent study examining axonal regeneration, it was shown that SLPI can overcome the inhibitory effects of the CNS myelin protein’s myelin-associated glycoprotein (MAG) and Nogo and enhance neurite outgrowth for several different neuronal populations in vitro (Hannila et al. 2013). Following optic nerve crush in rats, regeneration of retinal ganglion cell axons was significantly increased when the animals received intravitreal injections of SLPI, and this was the first evidence that in vivo delivery of exogenous SLPI can promote regeneration of transected CNS axons. Mechanistically, administration of SLPI following spinal cord contusion resulted in increased expression of IκBα and decreased TNFα levels within the tissue, which provides further evidence that SLPI inhibits the expression of pro-inflammatory cytokines by modulating NF-κB activity (Ghasemlou et al. 2010). In the regeneration study, it was shown that SLPI localizes to the nuclei of neurons, binds to the promoter for Smad2 – a TGFβ signaling protein – and decreases Smad2 protein levels, leading to enhanced axonal growth (Hannila et al. 2013). Based on these findings and those of the cerebral ischemia studies, it appears that SLPI promotes neuronal survival and regeneration by downregulating the expression of genes that negatively affect these processes.

In the last 7 years, several groups have started to explore the role of SLPI in neurodegenerative diseases such as multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and frontotemporal lobar degeneration (FTLD). Given its ability to suppress inflammation, it is not surprising that SLPI has been studied in experimental autoimmune encephalomyelitis (EAE), a rodent model of MS. SLPI was highly expressed in neurons, astrocytes, and microglia in all three phases of EAE, and intriguingly, SLPI also stimulated the proliferation and differentiation of neural stem cells into oligodendrocytes, which suggests that it could be capable of facilitating remyelination (Mueller et al. 2008). In the G93A mouse model of ALS, high levels of SLPI were present in the CNS and skeletal muscle of the animals, and the progression of the disease coincided with increased expression of SLPI in skeletal muscle (Lilo et al. 2013). Elevated levels of SLPI were also present in bone marrow mesenchymal stem cells obtained from patients with sporadic ALS, leading the authors to propose that SLPI could potentially serve as an ALS biomarker (Lilo et al. 2013). The newest development in this field has come from a study of an Italian FTLD cohort in which the affected patients were carriers of progranulin mutations (Ghidoni et al. 2014). As noted above, SLPI interacts directly with progranulin, and among these patients, the individuals with the highest plasma levels of SLPI showed a delay in the onset of the disease. This led to the conclusion that SLPI regulates the penetrance of this phenotype, and it raises the possibility that there may be a correlation between SLPI expression and the development of other inherited forms of dementia.


SLPI has always been regarded as a protease inhibitor, but it is now apparent that its biological function is considerably more complex. As research into this protein has expanded from basic biochemistry to studies of systemic disease, one observation that has been consistently reported is that SLPI regulates the expression of genes. The binding of SLPI to DNA underlies its ability to reduce inflammation and promote axonal regeneration and could also account for its antibacterial effects and enhancement of metastasis. It is therefore likely that SLPI regulates the expression of many other genes within the mammalian genome and affects a variety of physiological and pathophysiological processes. As we learn more about these effects, our perception of this protein will undoubtedly continue to change, and in the future, perhaps SLPI will be known primarily as a transcriptional regulator.


  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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedGoogle 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.PubMedCrossRefGoogle 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.PubMedGoogle 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.PubMedCrossRefGoogle 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.PubMedPubMedCentralGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle Scholar

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.University of ManitobaWinnipegCanada