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* Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia, USA; and
Drug Safety Research Laboratory, Daiichi Pharmaceutical Company, Tokyo, Japan
1Correspondence: Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health MS 3014, 1095 Willowdale Rd., Morgantown, WV 26505, USA. E-mail: myl6{at}cdc.gov
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: inflammation • cytokines • gene therapy
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. The restoration or augmentation
of cutaneous wound healing has long been an elusive goal for health
care professionals.
Skin wound repair in most mammals follows a similar orderly sequence of
events that are well known and have been thoroughly reviewed elsewhere
(2)
. The inflammatory response, which precedes wound
healing, is thought to be primarily involved in stemming infection and
removal of cellular debris. However, indirect evidence suggests that
inflammatory cytokines may be involved in modulating the healing
process. For instance, glucocorticoids decrease the expression of
proinflammatory cytokines in wounds and interfere with wound repair
(3)
. Furthermore, elimination of macrophages, a major
source of cytokines, from a wounded site delays wound healing
(4)
. A study by Fahey et al. (5)
demonstrated
an association in streptozotocin-induced diabetic mice between lower
levels of IL-6 in wound fluids and impaired wound healing. Impaired
wound healing is a common complication among individuals with diabetes
mellitus (6)
. IL-6 expression in dermal fibroblasts also
decreases with age, which may contribute to delayed cutaneous wound
healing in the elderly (7)
.
IL-6 is a pleiotropic cytokine that is involved in the growth and
differentiation of numerous cell types (8)
. It is readily
detected in cutaneous wounds (3
, 9)
and in the skin is
produced primarily by epidermal keratinocytes, whereas macrophages,
Langerhans’ cells, and fibroblasts in the dermis represent minor
sources of the cytokine (10)
. IL-6 is mitogenic for
keratinocytes (11
12
13)
and increased levels have been
associated with a number of skin pathologies, such as psoriasis
(12)
, scleroderma (14)
, and systemic lupus
erythematosus (15)
. Overexpression of IL-6 in the skin of
normal rats induces epidermal proliferation and inflammation
(13)
, whereas transgenic mice overexpressing IL-6 display
little more than a thickened stratum corneum (16)
.
Although it seems that the role of IL-6 is well established in disease
conditions, little is known about its role in skin repair.
It is well known that cutaneous healing in mice and rats is very
similar to humans, and mice are a well-characterized model of human
wound healing (5
, 9
, 17)
. In this study, we describe the
role of IL-6 in the mouse using a punch biopsy model of skin wound
healing. The punch biopsy method offers a convenient model to assess
wound closure, re-epithelialization, and granulation tissue formation.
We also investigate the use of recombinant protein and gene therapy as
therapeutic interventions in delayed wound healing.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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weighing 22–28 g and 
8 to 12 wk old
were housed in polycarbonate cages containing hardwood chip bedding at
room temperature (21±2°C) on a 12-h light-dark cycle. Mice were
anesthetized by i.p. injection with 80 mg/kg pentobarbital, and the
left flank was clipped and swabbed with Betadine (Purdue Frederick,
Norwalk, Conn.) and 70% ethanol three times before wounding.
Four-millimeter punch biopsies were performed on the shaved area.
Glucocorticoid-treated wild-type mice were dosed with 1 mg/kg/day s.c.
for 7 days before, and each subsequent day after, wounding. After
various healing periods, wounds were photographed or wound tissue was
collected (2–3 mm border was excised around the wound) and preserved
by flash-freezing for other studies or in buffered formalin for
histology. Histological sections were stained with Hematoxylin and
Eosin unless otherwise noted.
Determination of IL-6 mRNA expression by in situ
hybridization
In situ hybridization was performed as a modification
of the method of Howie (19)
. Briefly, paraffin-embedded
formalin-fixed tissues were dewaxed in xylene, rehydrated in ascending
alcohols, and digested for 1 h at 37°C in proteinase K (1
µg/ml). The slides were fixed in 0.4% paraformaldehyde in PBS for 20
min at 4°C. Twenty nanograms of biotinylated mIL-6 probe (R&D,
Minneapolis, Minn.) was added to 50 µl of hybridization buffer (0.6M
NaCl, 0.1% sodium pyrophosphate, 0.2% polyvinylpyrrolidine, 0.2%
Ficoll, 5 mM EDTA, 50 mM Tris-HCl, 10% dextran sulfate, 10% sheared
salmon sperm DNA, 50% formamide, pH 7.6). The slides were then
incubated at 37°C in a humid atmosphere for 16 h with the probe
solution. After incubation, the slides were washed under decreasingly
stringent conditions in sodium citrate buffer. Slides were washed in
tris buffered saline for 15 min and twice in buffer #1 (100 mM Tris
HCl, 150 mM NaCl, pH7.4) for 5 min. The slides were blocked in buffer
#1 containing 3% normal goat serum, (#S-1000, Vector, Burlingame,
Calif) for 30 min. The slides were incubated for 5 h at room
temperature in a humid chamber with a 1:2000 dilution of nutri-avidine
alkaline phosphatase conjugate (Pierce, Rockford, Ill.) in blocking
buffer. The slides were washed twice for 10 min and developed overnight
in NBT/BCIP solution (Sigma, St. Louis, Mo.) containing 0.5%
levamisole (Vector). After development, the slides were rinsed in
dH2O, dried and coverslips mounted.
In vivo AP-1 expression
Male mice carrying the AP1-luciferase transgene (graciously
provided by Drs. M. Ding and V. Vallyathan, CDC/NIOSH, Morgantown,
W.V.), originally developed by Rincon and Flavell (20)
,
were crossed with DBA2 (SASCO, Omaha, Nebr.) female mice as described
previously (21)
. The F1 offspring were screened by
quantifying both basal- and TPA-induced levels of luciferase activity
as an indicator for the presence of the AP-1-luciferase reporter gene.
AP-1 transgenic mice were wounded as described. Tissue from wounded and
nonwounded sites were taken from mice 16 h after wounding and
placed in lysis buffer (200 µl/10 mg tissue) overnight at 4°C. The
luciferase activity of the tissue supernatant obtained after lysis was
measured by a luminometer.
EMSA
Transcription factor DNA binding activity was determined by a
modification of the gel electrophoresis DNA binding assay described by
Schreiber et al. (22)
. Briefly, AP-1 and Stat 3
oligonucleotide (Santa Cruz Biotech, Santa Cruz, Calif.) was labeled
with 
32P-ATP (NEN/Dupont, Boston, Mass.) using
6–10 U of T4 polynucleotide kinase (USB/Amersham, Cleveland, Ohio).
The reaction mixture contained 40 µg of nuclear protein in 20 mM
Hepes, pH 7.9, 4% Ficoll 400, 50 mM KCl, 1 mM EDTA, 1 mM DTT, 0.25
mg/ml bovine serum albumin, 0.1 mg/ml of sheared salmon sperm DNA, and
0.1 ng (2x105 cpm) of specific probe.
Protein-DNA complexes were separated on a 4% nondenaturing
polyacrylamide gel. The gels were electrophoresed at 125V in 50 mM Tris
borate-EDTA buffer, dried, and exposed to a phosphorimager screen. For
characterization of DNA-binding activity, the nuclear protein extracts
were preincubated for 10 min before the addition of labeled probe with
a 100-fold excess of unlabeled wild-type or mutant oligonucleotide.
Nuclear protein from the liver of a C57BL/6 mouse exposed to 0.1 ml/kg
of carbon tetrachloride was used as a positive control. This procedure
has been shown to induce abundant AP-1 translocation in the liver
(23)
.
Murine IL-6 expression plasmid
The full-length murine IL-6 cDNA from a wild-type mouse liver
total RNA was amplified by PCR using the primers,
5'-gggaagcttcgctatgaagttcctctctgca and
5'-ggggaattccactaggtttgccgagtaga, which contain restriction sites for
EcoRI and HindIII. The resulting PCR product was
digested with EcoRI and gel purified (Qiagen, Valencia,
Calif.). The IL-6 fragment was ligated into the expression plasmid pCMV
(Stratagene, LaJolla, Calif.). XL1-blue supercompetent cells
(Stratagene) were transformed with the resulting ligation reaction and
were cultured on LB agar plates containing 25 µg/ml kanamycin.
Colonies from the plate were grown in LB broth containing 25 µg/ml
kanamycin, and plasmid was purified from each culture. Each plasmid was
assessed for the presence of the IL-6 insert via PCR, restriction
enzyme digestion, and dideoxy sequence analysis. Plasmids containing
the proper murine IL-6 gene were assessed for activity by injecting 40
µg of the plasmid intradermally into IL-6 KO mice. One plasmid
(pCMVIL-6.2) was identified to have a sufficient level of expression in
mouse skin.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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vs. 1b
), histology (Figs. 1c
, d
, e
, f
), and wound area
(mm2) (Fig. 2a
). IL-6 KO mice displayed significantly decreased
inflammation, granulation tissue formation, microvascularization, and
incomplete re-epithelialization (Fig. 1e
, f
). This impairment was noted for as long as 15 days,
nearly triple the normal healing time (Fig. 2a
).
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Localization of IL-6 mRNA synthesis in wound tissue
In situ hybridization was performed on sections of skin
wound tissue from wild-type mice to localize IL-6 mRNA expression in
cutaneous wounds. Figure 2b
shows that IL-6 is expressed in
epithelial keratinocytes at the wound edges and in macrophages and
fibroblasts in the dermis (Fig. 2d
). Epithelial IL-6
expression was not apparent distally from the wound, nor was there
appreciable IL-6 expression in unwounded skin sections (not shown).
IL-6 KO mice did not express IL-6 in either the dermis or epidermis of
cutaneous wounds (not shown).
Transcriptional activation associated with IL-6
The activation of the transcription factors AP-1, CEBP/ß, and
STAT 3 is associated with IL-6 activity in various tissues. To
determine if AP-1 was activated in skin by wounding, transgenic mice
carrying a AP1-luciferase transgene were wounded and luciferase
activity was assessed. On average, luciferase activity was 1,500-fold
higher in wounded skin than in intact skin (Fig. 3a
). To further characterize transcriptional events after
wounding, electrophoretic mobility shift assays (EMSA) were performed
on cutaneous wound tissue from wild-type and IL-6 KO mice. Significant
AP-1 activation occurred in wild-type mice 16 h after wounding,
which was not manifested in IL-6 KO mice (Fig. 3b
). However,
activation of Stat 3 was not apparent in wounded or nonwounded skin
from either wild-type or IL-6 KO mice (Fig. 3c
). C/EBP
(NF-IL-6) activation was also examined but not found to differ between
wild-type and IL-6 KO mice at the time points examined (not shown).
|
The effect of rmIL-6 or IL-6 gene therapy on wound healing in IL-6
KO mice
IL-6 KO mice were administered 1 mg/kg s.c. of rmIL-6 1 h
before wounding. This dose was shown previously to induce liver
regeneration in IL-6 KO mice after partial hepatectomy
(24)
. Treatment with rmIL-6 allowed healing to occur at a
similar rate to that in wild-type mice. Histological examination
revealed that wounds in rmIL-6–treated IL-6 KO mice re-epithelialized
normally and had well-formed granulation tissue (Fig. 4a
, b
). Reversal of delayed wound healing in IL-6
KO mice was also evaluated after injection of a mammalian expression
plasmid construct containing the full-length murine IL-6 cDNA linked to
a CMV promoter (pCMVIL-6.2). IL-6 mRNA was expressed at levels
detectable by RT-PCR when 40–50 µg of plasmid was injected
intradermally into IL-6 KO mice (not shown). When injected with 50 µg
of pCMVIL-6.2 16 h before wounding, 60% of the mice displayed
wound closure 5 days later. Re-epithelialization and granulation tissue
formation in these mice was similar to wild-type or IL-6 KO mice
treated with rmIL-6 (Fig. 4c
). RT-PCR confirmed IL-6
expression only in those mice that healed (4 out of 6) and lack of
expression in those that displayed impaired healing (Fig. 4e
). IL-6 expression was no longer apparent in any of the
plasmid-treated mice 5 days after wounding, indicating the expected
transient nature of gene transfer in keratinocytes (not shown).
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The effect of rmIL-6 on wound healing in glucocorticoid-treated
wild-type mice
To determine if IL-6 alone could be of use to aid in wound
healing, mice were immunosuppressed by dosing with 1 mg/kg/day of
dexamethasone for 7 days before wounding and each day thereafter. This
dosing regimen has been shown to inhibit cytokine and growth factor
expression after cutaneous wounding (25)
. As shown in
Fig. 5
, a single dose of 1 mg/kg of rmIL-6 1h before wounding significantly
reduced wound area and healing time in mice treated with dexamethasone.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(26)
, and it
affects multiple processes that are related to wound healing. For
example, IL-6 is proinflammatory and, after wounding, increases
adhesion of neutrophils to dermal fibroblasts (27)
.
Several studies have reported that IL-6 is a mitogen for keratinocytes
in vitro (11
, 12)
and in vivo
(13)
. IL-6 may also assist wound healing indirectly by
modulation of growth factors or their receptors. In this respect, IL-6
induces KGF expression in fibroblasts (28
, 29)
and EGF
receptor in keratinocytes in vitro (30)
. When
overexpressed in normal rat skin, IL-6 induces TGF
(13)
, a potent keratinocyte mitogen, and TGF in turn
induces IL-6 in keratinocyte cultures, indicating a paracrine
interaction (31)
. Herein, we demonstrate that IL-6
expression is intimately involved in cutaneous wound healing, as IL-6KO
mice display impaired wound healing manifested as deficiencies in
re-epithelialization, granulation tissue formation, and inflammation.
Preliminary data suggest that the mechanism by which IL-6 controls
wound healing is indirect, involving the regulation of genes involved
in growth factor expression.
IL-6 has been associated with the activation of the transcription
factor AP-1 in liver (24)
, cultured fibroblasts
(32)
, and various cell lines (33)
. AP-1
translocation has also been linked to keratinocyte proliferation
(34
, 35)
. We observed that wounding is associated with
both AP-1 translocation and IL-6 expression, and their peak activity
coincides with similar kinetics 16 h after wounding (Fig. 3a
,3b
). However, there is another peak of AP-1
induction that occurs 2 h after wounding that is not associated
with IL-6 expression. It is possible that other inflammatory mediators,
possibly proinflammatory cytokines such as TNF- and IL-1, might
modulate early transcriptional activation during wound healing. TNF-
and IL-1ß are transiently induced immediately after cutaneous injury,
peaking at 3 h, after which both cytokines decrease to near basal
levels by 10 h (9)
. Both of these proinflammatory
cytokines induce AP-1 translocation in various tissues
(36)
and are readily induced in the skin of normal and
IL-6 KO mice after wounding (Gallucci et al., unpublished
observations). In contrast, IL-6 is induced more slowly after wounding,
reaching maximal induction after 12 h before gradually returning
to basal levels after 24 h (9)
, thus coinciding with
AP-1.
The activation of Stat 3 (37
, 38)
and C/EBPß, similar to
AP-1, is associated with IL-6 stimulation in various tissues. However,
we observed that activation of Stat 3 and C/EBP does not differ between
wild-type or IL-6 KO mice during the early stages of cutaneous wound
healing (Fig. 3c
). This is consistent with earlier studies
suggesting that both Stat 3 (39)
and C/EBPß
(40
41
42
43)
are associated with differentiation, rather than
the proliferation of keratinocytes. Thus, these transcription factors
may be associated with the end stages of wound healing and is activated
only after re-epithelialization.
Transgenic animals can show variations in responses that are secondary
to the gene that was altered. To determine that the deficiencies noted
in wound healing were due in fact, to the lack of bioactive IL-6,
transgenic animals were reconstituted with rmIL-6 or a mammalian
expression plasmid containing consensus cDNA sequence for murine IL-6.
IL-6 KO mice treated with the recombinant cytokine (Fig. 4a
)
or IL-6 plasmid (Fig. 4c
) healed similarly to control mice,
indicating that IL-6 has a direct influence on wound healing that is
not associated with nonspecific phenotypic changes in IL-6 KO mice.
This is consistent with studies showing that IL-6 KO mice express
normal levels of functional IL-6 receptors (24
, 44)
.
It is well known that impaired cutaneous healing occurs in individuals
receiving glucocorticoids or other immunosuppressive therapies
(45)
. Although glucocorticoid treatment suppresses a host
of cytokines and growth factors, the role IL-6 plays in cutaneous
healing of immunosuppressed mice is not known. Herein we show that
rmIL-6 can significantly augment wound healing in dexamethasone-treated
mice (Fig. 5)
, indicating that IL-6 is a pivotal signal during wound
healing and a potential therapeutic for side effects associated with
immunosuppressive therapy. However, the wound-healing response was not
entirely restored by IL-6 treatment alone. Given the broad inhibitory
activity of glucocorticoids on cytokine expression, it is not unlikely
that other cytokines might cooperate with IL-6 in eliciting a complete
healing response.
Although possible side effects from IL-6 protein could make systemic
administration troublesome, local and transient expression of IL-6,
such as that produced in this model of gene therapy, would be more
promising because expression is transient and confined to the site of
administration, minimizing undesirable side effects. Intradermal
delivery of expression plasmid is not the most efficient method of gene
transfer into skin (46)
, as evidenced by the variations we
observed in IL-6 gene expression in our model (66% success rate).
However, the efficacy of gene transfer could be improved by the use of
other methods such as an adenovirus based viral vector, or
‘gene-gun’, which delivers microscopic particles coated with plasmid
directly into the tissue. Experiments designed to assess the
effectiveness of these treatments on immunosuppressed and diabetic
animal models are currently under investigation in this
laboratory.
Received for publication February 28, 2000.
Revision received May 5, 2000.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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= vehicle treated,
= dexamethasone treated, 
= dexamethasone + rmIL-6 treated.