Biology and clinical relevance of granulysin: REVIEW ARTICLE

Laboratory of Cellular and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4256, USA.
Tissue Antigens (Impact Factor: 2.14). 04/2009; 73(3):193-8. DOI: 10.1111/j.1399-0039.2008.01218.x
Source: PubMed


Granulysin is a cytolytic and proinflammatory molecule first identified by a screen for genes expressed 'late' (3-5 days) after activation of human peripheral blood mononuclear cells. Granulysin is present in cytolytic granules of cytotoxic T lymphocytes and natural killer cells. Granulysin is made in a 15-kDa form that is cleaved into a 9-kDa form at both the amino and the carboxy termini. The 15-kDa form is constitutively secreted, and its function remains poorly understood. The 9-kDa form is released by receptor-mediated granule exocytosis. Nine kiloDalton granulysin is broadly cytolytic against tumors and microbes, including gram-positive and gram-negative bacteria, fungi/yeast and parasites. It kills the causative agents of both tuberculosis and malaria. Granulysin is also a chemoattractant for T lymphocytes, monocytes and other inflammatory cells and activates the expression of a number of cytokines, including regulated upon activation T cell expressed and secreted (RANTES), monocyte chemoattractant protein (MCP)-1, MCP-3, macrophage inflammatory protein (MIP)-1 alpha, interleukin (IL)-10, IL-1, IL-6 and interferon (IFN)-alpha. Granulysin is implicated in a myriad of diseases including infection, cancer, transplantation, autoimmunity, skin and reproductive maladies. Small synthetic forms of granulysin are being developed as novel antibiotics. Studies of the full-length forms may give rise to new diagnostics and therapeutics for use in a wide variety of diseases.

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Available from: Alan M Krensky,
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    • "Cytotoxic granules of humans and some other mammals, but not rodents, also contain a saposin-like pore-forming protein, granulysin (GNLY), which preferentially disrupts cholesterolpoor bacterial, fungal and parasite membranes (Krensky and Clayberger, 2009; Stenger et al., 1998). Incubation of extracellular bacteria, including mycobacteria, with GNLY is cytolytic, but only using micromolar GNLY concentrations or extremely hypotonic or acidic buffers (Ernst et al., 2000; Stenger et al., 1998), suggesting that GNLY acts mostly against bacteria within acidic phagosomes or may act with other agents. "
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    ABSTRACT: When killer lymphocytes recognize infected cells, perforin delivers cytotoxic proteases (granzymes) into the target cell to trigger apoptosis. What happens to intracellular bacteria during this process is unclear. Human, but not rodent, cytotoxic granules also contain granulysin, an antimicrobial peptide. Here, we show that granulysin delivers granzymes into bacteria to kill diverse bacterial strains. In Escherichia coli, granzymes cleave electron transport chain complex I and oxidative stress defense proteins, generating reactive oxygen species (ROS) that rapidly kill bacteria. ROS scavengers and bacterial antioxidant protein overexpression inhibit bacterial death. Bacteria overexpressing a GzmB-uncleavable mutant of the complex I subunit nuoF or strains that lack complex I still die, but more slowly, suggesting that granzymes disrupt multiple vital bacterial pathways. Mice expressing transgenic granulysin are better able to clear Listeria monocytogenes. Thus killer cells play an unexpected role in bacterial defense.
    Cell 06/2014; 157(6):1309-1323. DOI:10.1016/j.cell.2014.03.062 · 32.24 Impact Factor
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    • "More importantly, RANTES was significantly increased in both the serum and urine in rats treated with ALT-803 plus BCG. RANTES is expressed and secreted by T-cells and promotes antitumor immunity by recruitment and activation of NK cells [43] and has been linked to IL-15 [44]. These induced immune responses observed following the intravesical treatment with ALT-803 plus BCG regimen were consistent with the observed effects of IL-15 on the host immune system when IL-15 was administrated intravenously [45]. "
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    ABSTRACT: Intravesical Bacillus Calmette-Guérin (BCG) has been shown to induce a specific immunologic response (i.e., activation of IL-2 and effector T-cells), while preclinical studies using ALT-803 (mutated IL-15 analogue combined with IL-15Rα-Fc fusion) have shown promising results by prolonging the agent's half-life and stimulating CD8+ T-cells. Based on these results, we hypothesized that the intravesical administration of ALT-803 along with BCG will generate an immunologic response leading to significant bladder tumor burden reduction. Using a well-established carcinogen induced rat non-muscle invasive bladder cancer (NMIBC) model, we studied the effects of intravesical ALT-803 with and without BCG. Rat tissues were evaluated to document treatment response. Intravesical ALT-803 was safe and well tolerated alone and in combination with BCG. As a single treatment agent, ALT-803 reduced tumor burden by 35% compared to control whereas BCG alone only reduced tumor burden by 15%. However, the combination of ALT-803 plus BCG reduced tumor burden by 46% compared to control. Immune monitoring suggested that the antitumor response was linked to the production and secretion of IL-1α, IL-1β and RANTES, which in turn, induced the proliferation and activation of NK cells. Lastly, tumoral responses of the combinational treatment were associated with 76% reduction in angiogenesis, which is significantly higher than when assessed with either agent alone. The enhanced therapeutic index seen with this duplet provides justification for the development of this regimen for future clinical trials.
    PLoS ONE 06/2014; 9(6):e96705. DOI:10.1371/journal.pone.0096705 · 3.23 Impact Factor
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    • "No significant difference in the plasma levels of other cytokines, such as IL-6 and tumor necrosis factor-a-a, was detected between HFSR patients and tolerant controls (Supplementary Figure S1a online). Of note, the level of granulysin, a cytotoxic protein identified as a key mediator of keratinocyte death in Stevens–Johnson syndrome and toxic epidermal necrolysis (Chung et al., 2008; Krensky and Clayberger, 2009), showed no difference between HFSR and controls (Supplementary Figure S1b online). The FasL levels in the blister fluids were significantly increased in the HFSR "
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    ABSTRACT: Sunitinib, a multi-targeted receptor tyrosine kinase inhibitor (TKI) used for the treatment of renal cell carcinoma and gastrointestinal stromal tumor (GIST), is notorious for cutaneous adverse effects, such as hand-foot skin reaction (HFSR). To explore the underlying mechanism of HFSR, we enrolled 53 sunitinib-treated GIST patients, including 23 HFSR cases, and 30 tolerant controls. Among 29 biomarkers examined, soluble FasL showed significant increase in the plasma, blister fluids, and skin lesions of HFSR patients. The plasma levels of sFasL were significantly correlated with that of sunitinib in HFSR patients. In addition to FasL, augmented expression of Fas and active caspase 3 was also detected in the epidermis of HFSR patients. The increased FasL caused keratinocyte death, as the use of anti-FasL antibody specifically blocked cell apoptosis. Oral administration of sunitinib to mice increased skin susceptibility to mechanical injuries in a dose/time-dependent manner. The administration of sunitinib (40 mg/kg/day) for 4 weeks to mice caused the maximally affected skin area with erosion to ulceration response to tape-stripping.The skin biopsies of mice given sunitinib exhibited increased expression of Fas and FasL in the apoptotic keratinocytes in the epidermis. Our data revealed that Fas/FasL interaction mediates keratinocyte death in sunitinib-induced HFSR.Journal of Investigative Dermatology accepted article preview online, 06 May 2014; doi:10.1038/jid.2014.218.
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