Biology and clinical relevance of granulysin: REVIEW ARTICLE

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DOI: 10.1111/j.1399-0039.2008.01218.x · Source: PubMed
Abstract
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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Tissue Antigens ISSN 0001-2815
REVIEW ARTICLE
Biology and clinical relevance of granulysin
A. M. Krensky & C. Clayberger
Laboratory of Cellular and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Key words
antibiotics; cytolytic T lymphocytes;
granulysin; immunotherapeutics; natural killer
cells
Correspondence
Alan M. Krensky
Laboratory of Cellular and Molecular Biology
National Cancer Institute
National Institutes of Health
37 Convent Drive, MSC 4256
Building 37/Room 2016
Bethesda
MD 20892-4256
USA
Tel: 11 301 728 2151
Fax: 11 301 496 8479
e-mail: krenskya@mail.nih.gov
Received 9 January 2009;
accepted 9 January 2009
doi: 10.1111/j.1399-0039.2008.01218.x
Abstract
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)-1a, interleukin (IL)-10, IL-1, IL-6 and
interferon (IFN)-a. 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.
Introduction
Granulysin is a cytolytic and proinflammatory molecule
expressed by activated human cytotoxic T lymphocytes
(CTLs) and natural killer (NK) cells (1). It was first
identified by subtractive hybridization in a search for genes
expressed by human T lymphocytes ‘late’ (3–5 days) after
activation (2). Based on sequence homologies with sphin-
golipid hydrolase activators of the central nervous system,
saposins A–D, it is a member of the saposin-like protein
(SAPLIP) family of proteins (3, 4) (Table 1). The SAPLIP
family members amoebapores A–C (Entamoeba histolytica
pore-forming proteins) and NK-lysin (a porcine lytic
granule protein) exhibit lytic activity, suggesting that
granulysin might also be cytolytic.
Cytolytic activity
Granulysin is found in cytolytic granules in CTL and NK
cells along with the pore-forming protein, perforin, and
granzymes (4, 5). It is synthesized as a 15-kDa molecule, and
portions are then cleaved at the amino and carboxy termini
to produce a 9-kDa form (4). Equivalent amounts of these
two forms of granulysin are found in CTL and NK cells.
However, the 9-kDa form is sequestered in cytolytic
granules, while the 15-kDa form is constitutively secreted
(6). Recombinant 9 kDa granulysin is dependent on per-
forin for killing intracellular pathogens (5). Recombinant
9 kDa granulysin is tumoricidal and broadly antimicrobial,
killing gram-positive and gram-negative bacteria, yeast,
fungi and parasites (5). Granulysin kills Mycobacterium
tuberculosis, the causative agent in tuberculosis (5), and
Plasmodium falciparum, a cause of malaria (7).
Tumor lysis by granulysin
Recombinant 9 kDa granulysin is broadly tumoricidal.
Extensive studies of recombinant granulysin lysis of Jurkat,
a human model tumor, are summarized in Figure 1.
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193
Granulysin binds to the tumor cell surface based on charge
(8). There is no evidence to date for a specific receptor for
cytotoxicity. Granulysin appears to scissor through the cell
membrane, causing ion fluxes (8, 9). Cytosolic calcium levels
increase as a result of an influx of extracellular calcium and
a release of calcium from intracellular stores, while cytosolic
potassium levels decrease as a result of activation of
a calcium-dependent potassium pump (10). Addition of
agents that block either the increase in intracellular calcium
or the decrease in intracellular potassium prevents activa-
tion of subsequent cell death pathways, and no tumor lysis
occurs. The increase in intracellular calcium, decrease in
potassium and the presence of granulysin (if ATP is present)
all contribute to mitochondrial damage. Mitochondrial
calcium overload disrupts the Krebs cycle and oxidative
phosphorylation. Megachannels are opened, giving rise to
release of both cytochrome c and apoptosis-inducing factor
(AIF). Electron transport is blocked and reactive oxygen
species increase. Cytochrome c release activates a caspase
cascade, which together with AIF induces endonuclease
Figure 1 Mechanism of tumor lysis by granuly-
sin. The model depicts the mechanism of tumor
lysis by granulysin. See Tumor lysis by granulysin
section for details. AIF, apoptosis-inducing factor.
Reprinted from Current Opinions in Immunology,
vol 15, Clayberger C, Krensky AM. Granulysin. pp.
560-565. Copyright (2003), with permission from
Elsevier.
Table 1 SAPLIP (saposin-like proteins) family members, proposed functions and organisms
Granulysin Antimicrobial and cytolytic; proinflammatory mediator Human
NK-lysin Granulysin orthologue Pig
Bovine lysin Granulysin orthologue Cow
Equus lysin Granulysin orthologue Horse
Saposin A Sphingolipid catabolism Human and others
Saposin B Sphingolipid catabolism Human and others
Saposin C Sphingolipid catabolism and lipid antigen presentation Human and others
Saposin D Sphingolipid catabolism Human and others
Pulmonary surfactant protein B Surfactant stabilization Human and others
Acyloxyacl hydrolase Phagocytic cell lipase; LPS deacetylation Human and rat
Acid sphingomyelinase Sphingolipid hydrolase Human and others
Prosaposin Neurite outgrowth; apoptosis; lipid transfer Human and others
Myosin regulatory light chain
interacting saposin-like protein (MSAP)
Glioma motility; neurite outgrowth Human
Amoebapore A Antimicrobial and cytolytic Entamoeba histolytica
Amoebapore B Antimicrobial and cytolytic Entamoeba histolytica
Amoebapore C Antimicrobial and cytolytic Entamoeba histolytica
Amoebapore orthologues Amoebapore-like Entamoeba dispar; Entamoeba invadens
Naegleriapores Pore forming; antimicrobial; cytolytic Naegleria fowleri (amoeba)
Fasciola hepatica saposin-like proteins Amoebapore-like Fasciola hepatica (liver fluke)
Clonorin Pore forming; antimicrobial; cytolytic Clonorchis sinensis (liver fluke)
J3-crystallin Eye lens protein; bridge lysosomal hydrolases
to lipids and activate enzyme activity
Tripedalia cystophora (cubom edusan jellyfish)
LPS, lipopolysaccharide.
Granulysin A. M. Krensky & C. Clayberger
194
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activation and standard apoptosis. This pathway occurs in
minutes (10).
In contrast, a slower cytotoxicity pathway is also induced
by granulysin as it activates a sphingomyelinase associated
with the cell membrane to generate ceramide (11). The
importance of this ceramide pathway remains unclear.
Granulysin killing of microbes
Recombinant 9 kDa granulysin is broadly antimicrobial (5,
12). Its mechanism of action appears to mimic tumor lysis,
interrupting oxidative metabolism and energy generation by
the organism. The cell wall is damaged and lipid metabolism
disrupted in M. tuberculosis.
Additional activities of granulysin
Chemotaxis
Like defensins, which have both cytotoxic and proinflam-
matory functions, granulysin is a chemoattractant for
a variety of cell types (12). Recombinant 9 kDa granulysin
attracts T cells, monocytic and NK-cell tumor lines but not
Epstein-Barr virus-transformed B-cell lines. Granulysin
shows maximal chemotactic activity for CD4
1
and CD8
1
T cells and monocytes at 10 nM. Chemotaxis is inhibited by
pertussis toxin, suggesting involvement of a G-protein
coupled receptor, but the identity of the receptor(s) remains
unknown.
Additional proinflammatory activities
In addition to chemotaxis, recombinant 9 kDa granulysin
induces expression of a number of proinflammatory cyto-
kines in monocytes and related tumor cell lines (U937),
including RANTES, MCP-1, MCP-3, MIP-1a, IL-10, IL-1,
IL-6 and IFN-a but not CD14, X-ray repair cross
complementing protein 1 (XRCC-1), chemokine (C-X-C
motif) receptor 4 (CXCR-4) or TNF-a (12).
Clinical importance of granulysin
Granulysin has broad clinical relevance to a myriad of
diseases, including infections, cancer, transplantation, skin
afflictions and reproductive complications.
Infectious diseases
Granulysin has been implicated in mycobacterial diseases
and malaria. Relatively, recent experiments with gene-
deleted mice (b2m, IFN-g, perforin, Fas/FasL, reviewed in
13) and the characterization of CTL lines from patients
indicate an important role for CTL in immunity to
tuberculosis (13). With Modlin, Stenger and others, we
identified a granulysin/perforin-mediated pathway respon-
sible for protection against intracellular pathogens, includ-
ing M. tuberculosis (5). Granulysin is present in granulomas
in tuberculosis, and its expression is highly correlated with
a curative host response and outcome (14). Children with
tuberculosis show decreased serum granulysin levels that
reverse with therapy (15). CD8
1
T cells coordinately express
CCL5 (RANTES), granulysin and perforin in tuberculosis
(16). CCL5 attracts infected macrophages, and perforin and
granulysin coordinate to kill the intracellular organism.
Granulysin is highly active against both drug-resistant and
drug-sensitive M. tuberculosis clinical isolates (17). There is
impaired expression of perforin and granulysin in CD8
1
T
lymphocytes at the site of infection in chronic pulmonary
tuberculosis patients (18). Recently, Klucar et al. showed
that CD4
1
T cells can lyse M. tuberculosis-infected target
cells and that both perforin and granulysin contribute to
lysis and inhibition of mycobacterial growth (19). Human
natural killer T (NKT) cells express granulysin and exhibit
antimycobacterial activity (20). Mycobacterium bovis Bacil-
lus Calmette-Guerin (BCG) vaccination induces memory
CD4
1
T cells in cows with enhanced expression of
granulysin homologue and perforin (21). Eukaryotic
expression of granulysin in mice is protective against
M. tuberculosis (22).
In a detailed examination of granulysin expression in
leprosy, granulysin-expressing cells were detected in cuta-
neous leprosy lesions at a sixfold greater frequency in
patients with the localized form of the disease (tuberculoid)
compared with the disseminated (lepromatous) form of the
disease (23). By contrast, perforin expression was similar
across all spectra of the disease. Unexpectedly, within the
leprosy granulomas, granulysin was found in CD4
1
T cells,
while the perforin was in the CD8
1
T cells. These findings
suggest a likely hypothesis: when the same effector cell
expresses both perforin and granulysin, the Mycobacterium
leprae is destroyed and there is no disease. When different
cells express granulysin and perforin, the microbe is walled
off in a granuloma. If there is little or no granulysin found,
the disease disseminates.
Farouk et al. showed that gd T cells inhibit growth of
the asexual blood stages of P. falciparum,acausative
agent for malar ia, by a granule e xocytosis pathway
dependent on granulysin expression (7). The inhibitory
capacity of effector T cells strongly correlated with
granulysin expre ssion in their cytotoxic granules. Zheng
et al. showed granulysin-mediated killing of t he fungus
Cryptococcus neoformans by granulysin in cytotoxic CD4
1
T cells (24). Fur thermore, this pathway is defective i n
patients with HIV.
Cancer
Granulysin expression has been widely correlated with good
outcomes in a variety of cancers. Low intracellular
expression of granulysin, but not perforin, in CD3-CD16
1
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195
A. M. Krensky & C. Clayberger Granulysin
cells correlates with progression of cancer (25). Flow
cytometric analysis showed high levels of both perforin
and granulysin in the NK cells in normal healthy controls.
Tumor-free patients expressed granulysin at levels similar to
controls, while cancer patients exhibited significantly
decreased (P < 0.005) granulysin levels. In contrast, per-
forin levels were similar in all groups. This study suggests
that impaired expression of granulysin in circulating NK
cells correlates with tumor progression (25).
Additional studies indicate that granulysin expression in
tumor infiltrates is associated with good outcomes. Pages
et al. found low granulysin expression in effector memory T
cells in tumor infiltrates to correlate early metastasis and
poor survival rates, while high levels of granulysin cor-
related with good outcomes in colorectal carcinoma (26).
Others have suggested that granulysin expression is a useful
biomarker for outcomes in gastric carcinoma (27) and
neuroblastoma (28). A Japanese group showed that ex-
pression of granulysin in a mouse model of small cell lung
cancer was protective (29).
Transplantation
Granulysin is also a useful biomarker in transplantation (1).
We showed that granulysin expression in situ is a marker for
acute rejection and steroid resistance (30). Kotsch et al.
reported that enhanced granulysin mRNA expression in
urinary sediment is the best biomarker for both early and
delayed renal allograft rejection (31). Hidalgo et al.
examining the ‘transcriptome’ of human cytotoxic T cells
found that granulysin was the most highly expressed
transcript in both CD8
1
and CD4
1
CTLs (32). In allo-
geneic, but not autologous, stem cell transplantation, serum
granulysin is transiently increased as measured by Enzyme-
Linked ImmunoSorbent Assay (ELISA) 3 weeks after
transplantation (33). Granulysin levels are markedly
increased and correlate with severity of graft vs host disease,
suggesting that it will be a useful biomarker in this context
as well.
Skin disease
Granulysin is an important mediator of damage in a variety
of skin diseases, including folliculitis (34), psoriasis (35),
acne (36), lichen planus (37) and viral vesicles (38). Most
recently, Chung et al. showed that granulysin is a key
mediator for disseminated keratinocyte death in both
Stevens–Johnson syndrome (SJS) and toxic epidermal
necrolysis (TEN) (39). Granulysin was present in CTL
and NK cells in the lesions, but the 15-kDa secretory form
was present in blister fluid as well. Intradermal injection
of recombinant 15 kDa granulysin caused skin necrosis
and blisters mimicking the clinical features of both SJS
and TEN.
Reproductive biology
Understanding of immune function of reproductive organs
is increasing, and granulysin has been found in endome-
trium (40), early pregnancy deciduas (41) and normal breast
epithelium (42). Plasma granulysin concentrations have
been associated with pre-eclampsia (43, 44).
A mouse transgenic for human granulysin
A standard approach to examine the in vivo function of
cytolytic molecules like granzymes and perforin has been to
disrupt expression of these genes in mice. Because mice do
not express granulysin or an apparent homologue, we
generated mice transgenic for human granulysin to establish
in vivo activity (45). In the first study, mice transgenic for
human granulysin were shown to reject C6VL, a T-cell
lymphoma of C57BL/6 origin, better than wild-type
littermates. This tumor rejection is dependent on CD8
1
T
cells. In contrast, protection against RMA-S, a mutant
lymphoma cell of C57BL/6 origin that is defective in peptide
loading of major histocompatibility complex (MHC) class I
and that is rejected by NK cells, was identical in granulysin
transgenic and control animals. This parallels studies in
human effector cell lysis of C. neoformans in which CD8
1
T-
cell-mediated killing is granulysin dependent, but NK-cell-
mediated killing is not (46, 47). Rather, NK cell killing of
C. neoformans depends on perforin (46).
We are in the process of backcrossing the granulysin
transgenic animals onto perforin and granzyme knockouts
and onto Balb/c gene backgrounds. These animals will be
useful for a variety of in vivo studies.
Therapeutics based on granulysin
Granulysin has potential as a new therapeutic for cancer
and/or infectious diseases. To date, we have focused on the
generation of synthetic peptides that are broadly antimi-
crobial (48). Granulysin derivatives offer the opportunity to
be broad spectrum, fast acting, non-toxic to human cells and
inexpensive and easy to manufacture. As antibiotic resis-
tance increases in clinically important organisms like
M. tuberculosis and Staphylococcus aureus, we focused on
granulysin and its derivatives as new broad-spectrum
antibiotics.
A series of several hundred synthetic peptides were
examined (49, 50). This analysis indicated that the cysteine
residues in granulysin are important for lysis of mammalian
cells (tumors) but not bacteria. Substitution of some
arginine residues also abrogates lysis of mammalian cells
but not bacteria. Inclusion of some
D-amino acids disrupts
a-helices, abrogating mammalian cell lysis but not bacteria.
The approach has been to synthesize test variant peptides
for in vitro and in vivo evaluation. These studies have led to
196
Journal compilation Ó 2009 Blackwell Munksgaard Tissue Antigens 73, 193–198
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Granulysin A. M. Krensky & C. Clayberger
broad-spectrum lead compounds of improved activity and
stability.
These peptides have been evaluated in model systems of
Vibrio cholera in neonatal mice and S. aureus in wound
infections with encouraging results (49).
Summary
Granulysin is constitutively expressed by NK cells and after
activation in both CD8
1
and CD4
1
cytolytic T lympho-
cytes. Recombinant 9 kDa granulysin kills a variety of
bacteria, fungi, parasites and tumors. In concert with
perforin, it kills intracellular pathogens. Granulysin is also
a chemoattractant for subsets of leukocytes and can activate
both monocytes and dendritic cells. Mice transgenic for
granulysin have been generated to evaluate in vivo activity.
The first studies with these mice show increased tumor
rejection by CD8
1
T lymphocytes but no effect on NK-cell-
mediated tumor protection. Lastly, synthetic peptides based
on granulysin exhibit greatly enhanced activity and specificity
in vitro and in vivo. Together, these studies suggest that
granulysin may prove a useful diagnostic (biomarker) and/or
therapeutic for a wide variety of diseases.
Acknowledgment
This work was supported by the Intramural Program of the
National Institutes of Health, National Cancer Institute
and the Center for Cancer Research.
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No claim to original US government works
Granulysin A. M. Krensky & C. Clayberger
    • "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. "
    [Show abstract] [Hide abstract] 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.
    Full-text · Article · Jun 2014
    • "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]. "
    [Show abstract] [Hide abstract] 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.
    Full-text · Article · Jun 2014
    • "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 "
    [Show abstract] [Hide abstract] 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.
    Full-text · Article · May 2014
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