ORIGINAL ARTICLE

Skin Barrier Disruption by Sodium Lauryl

Sulfate-Exposure Alters the Expressions of Involucrin,
Transglutaminase 1, Profilaggrin, and Kallikreins
during the Repair Phase in Human Skin In Vivo
Hans Torma1, Magnus Lindberg2 and Berit Berne1
Detergents are skin irritants affecting keratinocytes. In this study, healthy volunteers were exposed to water
(vehicle) and 1% sodium lauryl sulfate (SLS) under occlusive patch tests for 24 hours. The messenger RNA
(mRNA) expression of keratinocyte differentiation markers and of enzymes involved in corneodesmosome
degradation was examined in skin biopsies (n 8) during the repair phase (6 hours to 7 days postexposure)
using real-time reverse-transcription PCR. It was found that the expression of involucrin was increased at
6 hours, but then rapidly normalized. The expression of transglutaminase 1 exhibited a twofold increase after
24 hours in the SLS-exposed skin. Profilaggrin was decreased after 6 hours. Later (47 days), the expression in
SLS-exposed areas was 450% above than in control areas. An increased and altered immunofluorescence
pattern of involucrin, transglutaminase 1, and filaggrin was also found (n 4). At 6 hours post-SLS exposure, the
mRNA expression of kallikrein-7 (KLK-7) and kallikrein-5 (KLK-5) was decreased by 50 and 75%, respectively, as
compared with control and water-exposed areas. Thereafter, the expression pattern of KLK-7 and KLK-5 was
normalized. Changes in protein expression of KLK-5 were also found. In conclusion, SLS-induced skin barrier
defects induce altered mRNA expression of keratinocyte differentiation markers and enzymes degrading
corneodesmosomes.
Journal of Investigative Dermatology (2008) 128, 12121219; doi:10.1038/sj.jid.5701170; published online 15 November 2007

INTRODUCTION
Non-allergic contact eczema, or irritant contact dermatitis, is
the most common type of contact eczema and a widespread
problem in the population. It is induced by exposure of the
skin to chemical, mechanical, or physical stimuli, which may
seriously interfere with structural, molecular, and biochemical events important for the normal functioning of the skin
(Willis and Lindberg, 2004).
The detergent sodium lauryl sulfate (SLS), a common
ingredient in soaps, shampoos, and other skin care products,
is also a common test substance for induction of skin barrier
1

Dermatology & Venereology Section, Department of Medical Sciences,

Uppsala University, Uppsala, Sweden and 2Department of Occupational and
Environmental Dermatology, Karolinska Institute and Stockholm County
Council, Norrbacka, Stockholm, Sweden
The work for this paper was performed in Uppsala, Sweden.

Correspondence: Dr Hans Torma, Section of Dermatology and Venereology,

Department of Medical Sciences, University Hospital, Uppsala, Stockholm
751-85, Sweden. E-mail: hans.torma@medsci.uu.se
Abbreviations: KLK-5, kallikrein 5 (stratum corneum tryptic enzyme); KLK-7,
kallikrein 7 (stratum corneum chymotryptic enzyme); mRNA, messenger
RNA; PBS, phosphate-buffered saline; QRT-PCR, quantitative real-time PCR;
RT, reverse transcription; SLS, sodium lauryl sulfate
Received 16 February 2007; revised 27 September 2007; accepted 1 October
2007; published online 15 November 2007

1212 Journal of Investigative Dermatology (2008), Volume 128

damage. The time, and quality, of the skin barrier repair is

often used as an indication of how well various treatments,
for example, emollients, affect this process. However,
knowledge regarding the molecular mechanisms underlying
barrier repair after chemically induced damage is still sparse,
although we know that altered keratinocyte differentiation
and/or desquamation is likely to occur. In reconstructed skin,
SLS induces expression of involucrin and transglutaminase
(Ponec and Kempenaar, 1995; Fletcher and Basketter, 2006).
Studies on normal human skin in vivo exist, but are few in
number (Le et al., 1995, 1997; Ekanayake-Mudiyanselage
et al., 1998; van Ruissen et al., 1998).
Recently, loss-of-function variants of the filaggrin gene
were identified in two skin disorders with defect skin barrier,
namely atopic dermatitis and ichthyosis vulgaris (Palmer
et al., 2006; Smith et al., 2006). However, only few studies
have investigated the filaggrin expression in human skin after
acute barrier disruption (Gerritsen et al., 1994; Elias et al.,
2002). In mouse skin, on the other hand, overexpression of
filaggrin has been shown to accelerate recovery after barrier
disruption (Presland et al., 2004), underlining the importance
of filaggrin for barrier homeostasis.
In this study, we examined the epidermal messenger RNA
(mRNA) expression of keratinocyte differentiation markers
(involucrin, transglutaminase 1, and filaggrin) and two
& 2007 The Society for Investigative Dermatology

Hans Torma et al.

SLS Affects the Skin Barrier In Vivo

enzymes involved in the desquamation process, kallikrein-7

(KLK-7) and kallikrein-5 (KLK-5), during the barrier repair
phase, after exposing healthy volunteers to 1% SLS. Also,
protein expression of involucrin, transglutaminase 1, and
filaggrin was examined.
RESULTS
mRNA expression of markers of keratinocyte differentiation and
desquamation during the repair phase in normal skin following
exposure to SLS

As shown in Figure 1a, the involucrin expression was clearly

elevated after exposure to SLS, as compared with waterexposed areas and control skin, at both 6 and 24 hours
postexposure, after which it became normalized. Transglutaminase 1 exhibited a significant increase only at 24 hours
after exposure to SLS, although a tendency toward increased
expression was observed, after exposure to both SLS and
water, at 6 hours (Figure 1b).
Profilaggrin expression, on the other hand, was strongly
reduced in SLS-exposed areas after 6 hours compared
with both control and water-exposed areas. It was normalized after 24 hours, followed by an increase at 4 days
(Figure 1c). Statistically significant changes in water-exposed
areas, in comparison to control skin, were not found,
although a 50% reduction in the expression was observed
at 6 hours.
Two serine proteases involved in the degradation of
corneodesmosomes KLK-7 and KLK-5 exhibited a reduction
at 6 hours, followed by normalization at 24 hours to 4 days

As shown in Figure 3ai, the involucrin expression in SLSexposed skin was clearly elevated in most suprabasal cells as
compared with control skin (at 24 hours) and water-exposed
areas, at both 24 hours and 3 days postexposure (Figure 3d
and Table 1). The expression was not normalized even after 8
days. Similar results were observed in all four volunteers (see
Table 1 for summary of results).
Transglutaminase staining was increased between
24 hours and 8 days after SLS exposure (Figure 4ai), but no
obvious change was found in water-exposed areas. The
staining in SLS-exposed skin (24 hours and 3 days postexposure) was found in deeper layers, but not in all suprabasal
cells (Figure 3f).
Filaggrin expression exhibited a similar, but delayed,
pattern as compared with involucrin and transglutaminase 1.
A major increase in expression was detected after 3 days,
involving several layers with nucleated cells (Figure 5f). No
significant changes were detected in water-exposed areas in
comparison with control skin. The very low mRNA levels of
profilaggrin after 6 hours, both in water and in SLS-exposed
skin, were not reflected at the protein level.
The KLK-5 staining exhibited similar pattern as reported
previously (Ekholm et al., 2000), when examining formalin-

0.0078

0.0078

1,000
800
600
400
200
0
H2O SLS
6 hours

Protein expression of involucrin, transglutaminase 1, filaggrin,

and KLK-5 during the repair phase in normal skin following
exposure to SLS

H2O SLS
24 hours

H2O SLS
4 days

H2O SLS
7 days

Transglutaminase 1 (% of control)

Involucrin (% of control)

0.0078

(Figure 2a and b). No significant effect of water occlusion was

observed.

300

200

100

0
H2O SLS
6 hours

Time (after removing chamber)

Profilaggrin (% of control)

0.0078

H2O SLS
24 hours

H2O SLS
4 days

H2O SLS
7 days

Time (after removing chamber)

0.0142

300

200

100

0
H2O SLS
H2O SLS
H2O SLS
H2O SLS
24 hours
4 days
7 days
6 hours
Time (after removing chamber)

Figure 1. The mRNA expression of markers of differentiation is altered in SLS-exposed skin. The transcripts examined were (a) involucrin;
(b) transglutaminase 1; and (c) profilaggrin. The values, calculated using geNORM software, are presented as percentage of non-exposed, non-occluded
normal skin (at 24 hours) after normalization to the expression of the two housekeeping genes cyclophilin and b-actin (n 8).

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Hans Torma et al.

SLS Affects the Skin Barrier In Vivo

200

0.0078

Kallikrein-5 (% of control)

Kallikrein-7 (% of control)

0.0391

150
100

50
0

H2O SLS
H2O SLS
H2O SLS
H2O SLS
6 hours
24 hours
4 days
7 days
Time (after removing chamber)

200
150
100
50
0
H2O SLS
H2O SLS
H2O SLS
H2O SLS
6 hours
24 hours
4 days
7 days
Time (after removing chamber)

Figure 2. The mRNA expression of the enzymes involved in corneodesmosome degradation, namely, kallikrein-7 (KLK-7) and kallikrein-5 (KLK-5), is
altered in SLS-exposed skin but not in water-exposed, normal human skin (n 8). The transcripts studied were (a) KLK-7 and (b) KLK-5. The values are
presented, were calculated as described in Figure 1. Outliers, identified using Grubbs test, are shown as asterisks.

Water

Non-occluded control

SLS

6 hours

24 hours

3 days

8 days

Figure 3. The protein expression of involucrin during the barrier repair phase in normal skin exposed to water and 1% SLS for 24 hours. Involucrin
expression is increased in SLS-exposed skin but not in water-exposed skin between 6 hours and 8 days. The expression was analyzed using immunofluorescence
and the specific involucrin staining (Texas Red) is shown in white. The different time points studied are 6 hours (a and b) and 24 hours (c and d); and
3 days (e and f) and 8 days (g and h) after terminating the 24-hour exposure to water or SLS. (i) A biopsy was also obtained from a non-occluded area after
24 hours. Representative staining of water- and SLS-exposed areas are shown in a, c, e, and g, and in b, d, f, and h, respectively. Bar 50 mm.

fixed biopsies obtained from normal skin (data not shown).

However, the pattern in our frozen biopsies was slightly
different with a less distinct staining in stratum granulosum and
also gave nuclear staining, especially in SLS-exposed skin. At
1214 Journal of Investigative Dermatology (2008), Volume 128

day 3, this nuclear staining in SLS-exposed skin was prominent

and the staining in stratum granulosum more or less absent
(Figure 6). The staining pattern in SLS-exposed skin was not
completely normalized at day 8 (data not shown).

Hans Torma et al.

SLS Affects the Skin Barrier In Vivo

Table 1. Protein expressions of involucrin, transglutaminase 1, and filaggrin and changes in TEWL in SLS-exposed
skin
Involucrin
Volunteer
1

6 hours
0

Transglutaminase 1
1 day

3 days

8 days

+++

++

6 hours
0

Filaggrin

1 day

3 days

8 days

++

++

++

6 hours

TEWL ratio
1 day

3 days

8 days

6 hours

(+)

++

ND

++

++

++

++

4.9

+++

+++

++

++

++

++

++

++

++

3.4

++

++

++

++

(+)

2.9

ND, not determined; SLS, sodium lauryl sulfate; TEWL, transepidermal water loss.
The scoring of protein expression was performed on two sections from each biopsy. Water-exposed skin did not differ from control (untreated) skin (data not
shown). TEWL was measured 6 hours after removing the Finn chambers. TEWL ratio was calculated as TEWLSLS-exposed areas/TEWLwater-exposed area (four
exposed areas from each subject were measured).
1
The immunofluorescence stainings from this volunteer are shown in Figures 35.
2
Scoring: 0, no difference; +++, major difference involving most suprabasal cells.

Non-occluded control

Water

SLS

6 hours

24 hours

3 days

8 days

Figure 4. The protein expression of transglutaminase 1 during the barrier repair phase in normal skin exposed to water and 1% SLS for 24 hours.
Transglutaminase 1 expression is increased in SLS-exposed skin but not in water-exposed skin between 24 hours and 3 days. The expression was analyzed using
immunofluorescence. The specific transglutaminase 1 staining (Texas Red) is shown in white. For details, see Figure 3. Bar 50 mm.

The differences in transepidermal water loss between SLSand water-exposed skin indicated that the degree of barrier
disruption was almost similar in these three volunteers
(Table 1).

DISCUSSION
In this study, we observed changes in the mRNA expression
of involucrin, transglutaminase 1, and profilaggrin during the
repair phase after skin barrier disruption induced by SLS.
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Hans Torma et al.

SLS Affects the Skin Barrier In Vivo

Water

Non-occluded control

SLS

6 hours

24 hours

3 days

8 days

50 m

Figure 5. The protein expression of filaggrin during the barrier repair phase in normal skin exposed to water and 1% SLS for 24 hours. Filaggrin expression
is increased in SLS-exposed skin, but not in water-exposed skin, especially after 3 days. The expression was analyzed using immunofluorescence.
The specific filaggrin staining (Texas Red) is shown in white. For details, see Figure 3. Bar 50 mm.

Non-occluded control

Water

SLS

Figure 6. The protein expression of kallikrein-5 (KLK-5) in normal skin at day 3 after a 24-hour exposure to water and 1% SLS. KLK-5 expression is
decreased in SLS-exposed skin, as compared to water-exposed skin and control skin. The expression was analyzed using immunofluorescence. The specific
KLK-5 staining (Texas Red) is shown in white. For details, see Figure 3.

These changes indicated an ordered cascade starting

with synthesis of the cornified envelope, followed by
synthesis of filaggrin. The synthesis of the envelope constituent involucrin preceded the synthesis of the enzyme
involved in the crosslinking of involucrin and other
proteins, whereas the formation of filaggrin occurred later,
with an overlap in time with that of involucrin and
transglutaminase 1. Similar changes were also found at the
protein level, but they were slightly delayed as
compared with the detected mRNA changes. It has been
reported that acute barrier perturbations reduce calcium
1216 Journal of Investigative Dermatology (2008), Volume 128

levels in the stratum granulosum (Menon et al., 1992),

resulting in decreased mRNA levels of involucrin, profilaggrin, and loricrin (Elias et al., 2002), without any major
changes in the protein levels of involucrin and loricrin.
Also, exposure to high relative humidity (480%) has been
reported to lower epidermal calcium levels, resulting in
decreased mRNA and protein levels of loricrin and profilaggrin (Elias et al., 2002). In this study, a nonsignificant
reduction in profilaggrin mRNA expression was found in
water-exposed skin, but without obvious changes in protein
expression.

Hans Torma et al.

SLS Affects the Skin Barrier In Vivo

Both KLK-7 and KLK-5 have been shown to cleave the

corneodesmosomal proteins corneodesmosin, desmoglein 1,
and desmocollin 1 (Hachem et al., 2005). The observed
reduction in the mRNA expression of KLK-7 and KLK-5 and
protein expression of KLK-5, after SLS exposure, has not been
reported previously in connection with acute barrier disruption. By contrast, in one study, acute barrier disruption by
repeated tape stripping of hairless mice increased epidermal
proteolytic activity, assessed using in situ zymography
(Hachem et al., 2006). This proteolytic activity was found
to be prohibited by addition of serine protease inhibitors,
suggesting the involvement of kallikreins, for example KLK-7.
The study was performed using tape stripping for skin barrier
disruption (Hachem et al., 2006), which most likely removes
most of the upper stratum corneum. After tape stripping, it is
probably of importance to reduce the desquamation, and thus
a reduction of KLK-7 and KLK-5 would be beneficial for the
barrier restoration. SLS, on the other hand, might affect both
keratinocyte differentiation and lipid content in stratum
corneum. Speculatively, owing to putative deficiency or
disorganization of the lipids in stratum corneum, the
reduction of proteases in stratum corneum might aid in
producing a compensatory thickened stratum corneum and
epidermis, which reduces the transepidermal water loss. It
has been shown that KLK-7 affects the lipid-processing
enzymes b-glucocerebrosidase and acid sphingomyelinase,
which suggests an additional function of this enzyme for the
barrier function (Hachem et al., 2005). The discrepancy
between our study and the study by Hachem et al. (2006)
could be due to differences between species and/or between
the experimental setups for disruption by tape stripping
and SLS.
Others have reported increased expression of involucrin
after acetone exposure of mice skin (Ekanayake-Mudiyanselage et al., 1998) and after SLS exposure of human skin in
vivo (Le et al., 1997; van Ruissen et al., 1998) and
reconstructed skin in vitro (Ponec and Kempenaar, 1995;
Fletcher and Basketter, 2006). The increased expression and
localization of the protein resembles that observed in lesional
skin of atopic dermatitis (Jensen et al., 2004). In fact, a
premature expression of both involucrin and filaggrin was
found in one study, detected not only in granular, but also in
spinous cells (Jensen et al., 2004). However, when the
protein expression of involucrin was further examined by
immunoblotting, the amount was found to be lower in
lesional skin than in normal and non-lesional skin (Jensen
et al., 2004). Whether this was the case also in SLS-exposed
skin was not examined in this study. The observed changes in
involucrin may not only have an impact on the synthesis of
the cornified envelope, but may also affect the formation of
lipid lamellae in stratum corneum, as ceramides are
covalently bound to cornified envelope proteins, mainly
involucrin (Marekov and Steinert, 1998).
The role of filaggrin for the skin barrier has been
emphasized by the loss-of-function variants of the profilaggrin gene in two skin disorders with defect barrier function,
atopic dermatitis and ichthyosis vulgaris (Palmer et al., 2006;
Smith et al., 2006). Also, overexpression of filaggrin in mouse

skin has been shown to accelerate recovery after barrier

disruption (Presland et al., 2004). Surprisingly, an inverted
correlation between dry skin phenotype and filaggrin repeat
number polymorphism has been reported (Ginger et al.,
2005). However, filaggrin is not only an intermediate
filament-associated protein that aggregates these filaments.
Keratinocytes induced to (over-) express moderate to high
levels of filaggrin in vitro exhibit altered distribution of actin
microfilaments and disrupted distribution of desmosome
proteins, suggesting an additional role(s) for this protein
during terminal differentiation of epidermal keratinocytes
(Presland et al., 2001). Some of these additional effects of
filaggrin may explain the abovementioned finding in dry skin
patients.
The clinical relevance of this finding is not clear. In vivo
exposure to this high concentration of SLS does not occur
very often. To examine whether similar changes occur during
repeated low-dose exposure, as in the daily life situation, we
need to use a different experimental design. It has previously
been suggested that with repeated exposure to an irritant or a
combination of varying irritants, the degree of impairment
surpasses a critical level, and as a consequence, a clinical
disease (irritant contact dermatitis) ensues (Malten, 1981).
This phenomenon could resemble the effects of a single dose
of SLS using high concentrations; however, a lack of
agreement has been reported between the acute effect and
the repeated tests for SLS, probably due to thickening of
epidermis during long-term exposure to this irritant (Koopman et al., 2004).
In conclusion, our present results demonstrate an altered
expression pattern of keratinocyte differentiation markers,
both at mRNA and at protein level, in skin exposed to SLS.
This implies that the recovery after SLS exposure is at least
partially due to increased, and premature, synthesis of
cornified cell envelope components and profilaggrin.
MATERIALS AND METHODS
Biological specimen
Healthy volunteers (five men and six women, 2052 years old)
without atopic background gave written informed consent to a
protocol approved by the Regional Ethical Review Board in Uppsala
and Department of Medical Sciences, Uppsala University, and
Uppsala University hospital, Sweden. The study was conducted
according to the Declaration of Helsinki Principles. Volunteers were
exposed to 50 ml 1% SLS (Sigma-Aldrich Sweden AB, Stockholm,
Sweden; purity approximately 99%) in water and vehicle control
(water) in large Finn chambers (11-mm diameter) on the buttocks for
24 hours. The side to be exposed to SLS was chosen by randomization. All chambers were removed after 24 hours. Punch biopsies
(3 mm) were obtained after 6 hours and 1, 4, and 7 days, after
infiltrating the areas with lidocain plus adrenaline (Xylocain;
Astra Zeneca, Sodertalje, Sweden). In addition, non-occluded,
untreated skin was also obtained at the same side as vehicle
controls on day 1.
The samples were stored in 0.5 ml RNAlater (Ambion Ltd,
Huntingdon, UK) at 4 1C for 2448 hours. The samples were
trimmed from the dermal side using a razor blade to remove excess
of dermis and stored dry at 20 1C until further processing.
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Hans Torma et al.

SLS Affects the Skin Barrier In Vivo

RNA extraction and reverse transcription

Statistical analysis

Total RNA was prepared by homogenizing the tissue in 1 ml Trizol

(Invitrogen, Carlsbad, CA) using a Polytron 2100 for two repeated
bursts of 15 seconds at setting 6. Between the samples, the pestle was
washed twice with 5 ml water and once with 2 ml Trizol. After
homogenizing the tissue, total RNA was isolated according to the
manufacturers protocol, after including 50 ng GlycoBlue (Ambion
Ltd). The concentration of total RNA was determined by spectrophotometry and first-strand complementary DNA was synthesized as
described previously (Torma et al., 2006).

The results are presented in box-and-whiskers graphs (Figures 1 and

2). The box is defined by the upper (Q3) and lower (Q1) quartiles
and the median is marked by a subdivision of the box. The whiskers
are the lines that extend from the top and bottom of the box to the
lowest and highest observations. Outliers, identified using Grubbs
test as at http://www.graphpad.com/quickcalcs/Grubbs1.cfm, are
shown as asterisks. Differences at various times after SLS removal
were analyzed by Wilcoxons signed rank test on paired data using
GraphPad Prism (version 4.03) software (San Diego, CA).

Quantitative real-time PCR

CONFLICT OF INTEREST

The PCRs were performed as previously described (Torma et al.,

2006). In brief, the number of transcripts was studied by quantitative
real-time PCR (QRT-PCR) in a 25 ml reaction, using complementary
DNA as template (E25 ng total RNA). The primers and probes were
obtained from Applied Biosystems, Stockholm, Sweden; the
sequences have been described elsewhere (Torma et al., 2006).
Triplicate reaction tubes were set up for each sample. The tubes
were placed in a MyiQ (BioRad Laboratories Inc., Hercules, CA)
programmed as described earlier (Torma et al., 2006). Simultaneous
amplification of known amounts of a PCR product generated a
standard curve for comparison. The expressions of the two housekeeping genes in each sample were converted into normalization
factors, to which the expression of the genes of interests was
normalized. The geNORM software (Center for Medical Genetics,
Ghent University, Ghent, Belgium) was used for these calculations
(Vandesompele et al., 2002).

The authors state no conflict of interest.

Immunofluorescence staining of SLS-exposed skin

Punch biopsies (3 mm) were obtained from four SLS-exposed
subjects, as above, after 6 hours, and 1, 3, and 8 days, and frozen
in isopentane. Following mounting in mounting media, 6 mm
sections were obtained. After an overnight block at 4 1C using
10% goat serum, primary mAb was added for 1 hour. The mAbs used
were involucrin at a 1:500 dilution (Medac, Wedel, Germany),
transglutaminase 1 at 1:100 dilution (Biomedical Technologies,
Stoughton, MA), and filaggrin at 1:200 dilution (Novocastra,
Newcastle upon Tyne, UK). The secondary antibody, biotinylated
anti-mouse immunoglobulin G (IgG) (Vector Laboratories Inc.,
Burlington, CA), diluted at 1:200, was added for 1 hour. In a third
step, the sections were incubated with streptavidin-conjugated Texas
Red (dilution 1/100; Vector Laboratories Inc.) for 1 hour. Rabbit
polyclonal against KLK-5 was obtained from Santa Cruz Biotechnology (Santa Cruz, CA). After blocking and incubation overnight at
4 1C with a 1:100 dilution of the KLK-5 antibody, the staining was
visualized using a goat anti-rabbit IgG Texas Red conjugated
secondary antibody. The sections were mounted using 40 -6diamidino-2-phenylindole-containing mounting medium for visualization of nuclei. The staining was visualized using a Zeiss Axiophot
microscope (Carl Zeiss AB, Stockholm, Sweden) equipped with an
Axiocam MRm camera (Carl Zeiss AB).

Transepidermal water loss measurements

Six hours following removal of occlusive patches, transepidermal
water loss (g/m2 per hour) was determined using a Vapometer
(Delfin Technologies, Kuopio, Finland).
1218 Journal of Investigative Dermatology (2008), Volume 128

ACKNOWLEDGMENTS
This work was supported by grants from the Edvard Welander and Finsen
foundations and the Swedish Council for Working Life and Social Research
(FAS). We thank Inger Pihl-Lundin for assistance in recruiting healthy
volunteers and performing the immunofluorescence stainings.

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