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*
Departments of Dermatology and
Pediatrics, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH 44106;
Department of Dermatology, Kyushu University, Fukuoka, Japan; and
§
Veterans Administration Medical Center, Cleveland, OH 44106
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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mRNA was also induced in a
similar microanatomic localization. To model the effects of these
complex signals on infiltrating Mo/Mph following UV exposure, we then
tested the effects of immobilized iC3b and TNF- on resting blood
monocytes. Both IL-10 mRNA synthesis and protein secretion were
significantly induced by binding of iC3b in vitro and were
synergistically increased by the presence of TNF-. The effect was
abrogated by a blocking Ab to CD11b, indicating CD11b-iC3b interaction.
In contrast, iC3b binding resulted in suppression of IL-12 p40 mRNA and
significantly inhibited the production of IL-12 p70 protein. Our
studies thus define a novel mechanism for induction of tissue Mo/Mph
into an IL-10high/IL-12low state via iC3b in
combination with TNF-. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We previously have shown that CD11b+ monocytic/macrophagic
cells (Mo/Mph)3 infiltrating
into UV-irradiated skin (15, 16) are responsible for immunosuppression
and tolerance induction in mice after UV irradiation (17, 18, 19). In
addition, we have reported that CD11b+ Mo/Mph are the major
source of IL-10 in UV-exposed human skin compared with keratinocytes
(20, 21). However, the mechanism of IL-10 induction by
CD11b+ Mo/Mph is not known. UV-induced Mo/Mph express high
levels of CD11b (CR3), a ß2 integrin containing an
-subunit with a binding motif in the I domain for iC3b, ICAM-1, and
fibrinogen (22, 23). We hypothesized that interaction of CD11b with its
ligand might regulate IL-10 production. Resting blood
CD11b+ monocytes produce only low or undetectable levels of
IL-10, but produce high levels of IL-10 in vivo after migration from
the microvasculature into UV-exposed skin (21). We focused our
attention on iC3b, as a potential ligand for CD11b, because we have
reported recently that blockade of CD11b and depletion of C3 in
UV-exposed murine skin reversed UV-induced immunosuppression,
indicating that complement is implicated in locally inducible UV
immunosuppression (18, 24). However, it has not been shown whether,
where, and when iC3b appears in UV-exposed human skin. Keratinocytes
are regarded as the most likely local source of C3 in the skin (25),
and complement regulatory proteins can be found in human skin (26).
Moreover, deposits of the C3 cleavage fragment C3d, g were shown at the
dermal-epidermal junction (DEJ) of normal skin (27), were up-regulated
in inflammatory diseases (28), and were observed in keratinocytes of
UV-irradiated skin (29), suggesting that this process accompanies skin
inflammation. Therefore, if iC3b is produced in UV-exposed skin,
binding of iC3b to ß2 integrin on Mo/Mph could affect the
production of immunoregulatory cytokines, such as IL-10 and IL-12, in
the post-UV milieu. Indeed, recent studies have shown that signaling
via CR3 plays an important role in regulating the production of IL-12
(30, 31).
Another key element that may be induced after UV exposure and
implicated in UV-induced immunosuppression is TNF- (32, 33). For
instance, it has been well documented that TNF- can be induced by
keratinocytes and dermal mast cells after UV irradiation (34, 35) and
is known to induce IL-10 in human monocytes in vitro (36).
Nevertheless, the localization of TNF- mRNA under in vivo conditions
has not yet been shown, particularly in relation to iC3b and Mo/Mph
localization.
In this study we demonstrate that iC3b deposits and TNF- mRNA are
induced in UV-exposed skin. Furthermore, we make the novel finding that
in vitro binding of iC3b to ß2 integrin on monocytes
up-regulates the production of IL-10; conversely, iC3b down-regulates
IL-12. IL-10, but not IL-12, production is enhanced by the addition of
TNF-. This model of the UV-induced microenvironment recapitulates
the cytokine profile of in vivo UV-induced Mo/Mph, which are
IL-10high/IL-12low, and provides insight into
mechanisms of UV-induced immunomodulation and monocyte-macrophage
differentiation in inflamed tissues.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Adult volunteers participated in this study after institutional review board approval of the protocol and informed consent. Punch biopsies were taken from buttock skin after four minimal erythema doses of UVB irradiation from Westinghouse FS20 bulbs (PSC Lamps, Pittsford, NY) at different time points.
Immunofluorescence microscopy studies
Six-micron frozen sections of biopsies of normal and UVB-irradiated skin were blocked with 10% goat serum/PBS and treated with primary mouse mAb for human iC3b (IgG2b, Quidel, San Diego, CA) or its isotype control IgG2b (Sigma, St. Louis, MO), diluted to 2 µg/ml in 10% goat serum/PBS for 1 h, followed by FITC-conjugated goat anti-mouse IgG2b secondary Ab (Caltag, San Francisco, CA). Double-immunofluorescence staining was performed using additional primary mouse mAb for human CD11b (BEAR 1, IgG1, Immunotech, Westbrook, ME), diluted to 2 µg/ml in 10% goat serum/PBS for 1 h, followed by biotin-conjugated goat anti-mouse IgG1 secondary Ab (Caltag) and rhodamine RedX-conjugated avidin (Molecular Probes, Eugene, OR). Slides were viewed and photographed by fluorescence microscopy (Axiophot, Carl Zeiss, Thornwood, NY).
In situ hybridization
In situ hybridization was performed as previously described (21, 37) with some modifications. Briefly, sections were cut, thaw-mounted on RNase-free poly-L-lysine-coated slides (Sigma), fixed in 4% paraformaldehyde/PBS, dehydrated in an ethanol series, and stored at -80°C. Slides were thawed, treated with proteinase K (Boehringer Mannheim, Indianapolis, IL), and prehybridized for 1–3 h at 42°C. Hybridization was performed overnight at 55°C by adding 1 µg/ml heat-denatured digoxigenin-labeled riboprobe (antisense or control sense). Sections were treated with 100 µg/ml RNase A and 1 µg/ml RNase T1 (both from Boehringer Mannheim) in 2x SSC (Research Genetics, Huntsville, AL) before incubation with alkaline phosphatase-conjugated Abs to digoxigenin and were detected as described previously (21).
cDNA for murine TNF- in pGEM transcription vector was used to
generate riboprobes for in situ hybridization. Mouse TNF- cDNA
representing the 700-bp fragment of TNF--coding sequence was a gift
from Dr. Bruce Beutler (University of Texas Southwestern Medical
School, Dallas, TX). The plasmid was linearized with the
appropriate restriction enzymes and was transcribed with SP6 or T7
polymerase in the presence of digoxigenin UTP (Genius kit 4, Boehringer
Mannheim) to generate digoxigenin-labeled control sense and antisense
RNA probes.
Isolation of human blood monocytes
PBMC were obtained by centrifugation of heparinized fresh
peripheral blood with Ficoll gradients (1.077; Sigma). After the
incubation of PBMC in tissue culture dishes for 1 h at 37°C,
adherent cells were harvested by 0.5 mM EDTA in HBSS (Life
Technologies, Grand Island, NY). Cells were treated with blocking Ab
(Fc
RII, anti-CD32) for 10 min on ice and incubated with Ab
mixture (anti-CD2, -3, -19, and -56 and glycophorin A) for 15 min
and with dextran-iron for 15 min (all from StemCell Technologies,
Vancouver, Canada), followed by adherence to a MACS separation column
against a MidiMACS magnet (Miltenyi Biotec, Auburn, CA). The purity of
negatively selected monocytes, as determined by flow cytometry, was
>90%.
Preparation of IgM- and iC3b-coated sheep erythrocytes
IgM-coated sheep erythrocytes (EA) and IgM- plus iC3b-coated sheep erythrocytes (EAiC3b) were prepared as previously described (22, 38) with some modifications. Briefly, EA were generated by incubating erythrocytes with anti-sheep erythrocyte IgM (produced by clone M1/81 · 27 · 7 from American Type Culture Collection, Manassas, VA) for 15 min at 30°C. Then C3b-coated EA was prepared by incubation of EA with C5-deficient human serum (Sigma) for 1 h at 37°C while rotating. The C3b was converted to iC3b by incubation with 1% fresh human serum for 1 h at 37°C. It has been reported that most of the C3b is converted to iC3b, and very little, if any, is degraded further to C3d using this method (38). The presence of iC3b on erythrocytes was verified by flow cytometry using anti-human iC3b or its isotype control IgG2b, followed by FITC-conjugated goat anti-human IgG2b. The expression of iC3b on EAiC3b was about 50-fold increased in fluorescence intensity relative to EA.
Determination of cytokine production by peripheral blood monocytes in response to iC3b
Purified monocytes were plated in six-well tissue culture dishes
(1.5–2.0 x 106/well) and incubated with medium alone
(RPMI 1640 (Life Technologies) plus 10% FBS (HyClone, Logan, UT)), EA,
or EAiC3b (erythrocyte:monocyte ratio of 25:1) for 1 h. Human
rTNF- (50 ng/ml; R&D Systems, Minneapolis, MA) and/or 0.001%
Pansorbin cells (Staphylococcus aureus cells (SAC);
Calbiochem-Novabiochem, La Jolla, CA) (39) were added in some wells and
were incubated for 20 h at 37°C. In some experiments, for
blocking of iC3b binding to CD11b, monocytes were treated with 25
µg/ml M1/70 Ab or its isotype control (IgG2b; both from
PharMingen, San Diego, CA) for 1 h before the incubation of EA
or EAC. Culture supernatants were harvested and stored at -70°C
until assayed, and pellets were subjected to RNA extraction.
RNA extraction and RT-PCR
RT-PCR was performed as previously described (20). Simply, monocyte RNA was extracted by RNeasy Total RNA Kits (Qiagen, Chatsworth, CA) and quantified by spectrophotometric measurement. cDNA was synthesized from 200 ng of total RNA. The primers used for amplification were as follows: human IL-10 (nucleotides 323–347 of the sense strand (5'-CTGAGAACCAAGACCCAGACATCAA-3') and nucleotides 648–674 of the antisense strand (5'-CAATAAGGTTTCTCAAGGGGCTGGGTC-3'); 352 bp), IL-12 p40 (nucleotides 806–822 of the sense strand (5'-CCACATTCCTACTTCTC-3') and nucleotides 1061–1077 of the antisense strand (5'-GTCTATTCCGTTGTGTC-3'); 272 bp), and ß-actin (447 bp). Thirty-two cycles were conducted in QuarterBath Thermal Cycler (Inotech, Lansing, MI) with denaturation at 94°C for 1 min, annealing at 55°C (60°C for ß-actin) for 1 min, and extension at 72°C for 2 min. PCR products were analyzed by electrophoresis with 1.5% agarose gel with ethidium bromide.
Quantification of protein by ELISA
Culture supernatants were assayed by ELISA using mAb pairs of rat anti-human IL-10 (JES3-9D7, IgG1) and biotin-conjugated rat anti-human IL-10 (JES3-12G8, IgG2a; both from PharMingen) for IL-10, and mouse anti-human IL-12 p70 (IgG) and biotin-conjugated mouse anti-human IL-12 (C8.6, IgG; both from Endogen, Cambridge, MA) for IL-12. Human rIL-10 (PharMingen) and rIL-12 (R&D Systems) were used as standards, respectively. Results are expressed as picograms per milliliter.
Statistical analysis
Statistical significance of differences was determined by Student’s t test where indicated.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We initiated immunofluorescence studies to investigate alteration
of iC3b production and Mo/Mph infiltration after UV exposure in vivo
(n = 3). Non-UV control skin and skin taken 6, 24, 48,
and 72 h after UV exposure were first stained with isotype control
(Fig. 1
a) or mAb specific for
iC3b (Fig. 1, b–f). Control skin and skin taken 6 h
after UV exposure showed very few iC3b deposits at the DEJ (Fig. 1, b and c, white arrows), whereas marked fine
granular iC3b deposits were induced in the DEJ of UV-exposed skin
taken at 24, 48, and 72 h (Fig. 1, d–f). In addition,
iC3b+ UV-damaged keratinocytes were identified after UV
exposure (Fig. 1, e and f, asterisks).
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, a and c; Fig. 2b is the isotype control). There were small numbers of
CD11b+ cells in control dermal skin (Fig. 2a,
white arrowhead). In contrast, UV-exposed skin taken at 48 h (Fig. 2c) revealed CD11b+ cells to be increased
markedly in the dermis; these cells were regularly observed to be in
physical apposition with the fine granular deposits of iC3b along the
DEJ (Fig. 2c, white arrows). In addition, CD11b+
cells that had migrated into the epidermis were in close contact with
epidermal iC3b+ keratinocytes. Although some of the
CD11b+ cells were neutrophils, it was confirmed that
mononuclear cells were the dominant leukocyte in UV-exposed skin using
hematoxylin eosin-stained sections (data not shown). No staining was
observed in UV-exposed skin treated with isotype control (Figs. 1
a and 2b).
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In situ hybridization with TNF- antisense riboprobes was also
performed in UV-exposed skin to evaluate the in vivo localization of
TNF- production (n = 3). In control unirradiated
skin, we detected only a few TNF-+ cells (Fig. 3a), whereas TNF- mRNA was
markedly induced in UV-exposed skin taken at 72 h (Fig. 3c). Many cells expressing TNF- in the epidermis along
the DEJ were keratinocytes with intracytoplasmic bridging (Fig. 3c, black arrows). Other TNF-+ cells were
seen around the vessels in the papillary dermis (Fig. 3c,
black arrowheads). UV-exposed skin treated with the sense riboprobe
(negative control) was negative (Fig. 3b).
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We hypothesized that binding of iC3b to ß2 integrin
on infiltrating Mo/Mph following UV exposure might be involved in the
regulation of IL-10 cytokine production. To elucidate the effect of
iC3b binding on monocyte cytokine production, monocytes were purified
from peripheral blood by negative selection, and EAiC3b were prepared.
The presence of CD11b on monocytes and iC3b on the cell surface of
erythrocytes was verified by flow cytometry (data not shown). Highly
purified monocytes (>90%) were incubated with medium alone, EA, or
EAiC3b for 20 h. Total monocyte RNA was then extracted, and RT-PCR
for IL-10 was performed (Fig. 4A). Monocyte IL-10 mRNA was
undetectable when incubated with medium alone or EA (Fig. 4A, lanes 1 and 3), whereas incubation
with EAiC3b resulted in IL-10 mRNA induction (Fig. 4A,lane 5). The secretion of IL-10 protein in the supernatant under
identical conditions was measured by ELISA (Fig. 4B). The
production of IL-10 was minimal in medium alone (<10 pg/ml) or when
incubated with EA, whereas IL-10 was significantly increased when
stimulated with EAiC3b in comparison with medium alone or EA (Fig. 4B; p < 0.01; n = 9). It is
unlikely that IL-10 production induced by EAiC3b, but not EA, was
caused by a low amount of endotoxin contamination because we used the
same buffer, IgM, erythrocytes, etc. to prepare EA and EAiC3b. The only
difference was the inclusion of C5-deficient serum and 1% human serum.
Nevertheless, we examined whether C5-deficient serum and 1% human
serum could stimulate IL-10 production. Neither stimulated IL-10
production upon incubation with fresh human monocytes under conditions
identical with those used for the iC3b experiments (data not shown).
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After UV exposure, TNF- mRNA is induced in vivo in the same
microanatomic areas as iC3b deposition and Mo/Mph infiltration, as
shown in Fig. 3. To further model the in vivo conditions in UV-exposed
skin, purified monocytes were incubated with medium alone, EA, or
EAiC3b in combination with 50 µg/ml TNF-. The appropriate
concentration of TNF- was determined in preliminary experiments
(data not shown). After 20-h incubation, RT-PCR and ELISA were
performed. Although TNF- alone induced small amounts of IL-10 mRNA
(Fig. 4A, lanes 2 and 4), the
combination of TNF- with iC3b resulted in potent induction of IL-10
mRNA (Fig. 4A, lane 6). Similarly, combined
exposure to both TNF- and iC3b resulted in a significant increase in
IL-10 protein secretion relative to that caused by EAiC3b alone,
TNF- alone, or TNF- plus EA (Fig. 4B;
p < 0.05).
Binding of iC3b to ß2 integrin on monocytes down-regulates IL-12 mRNA synthesis and protein secretion
To evaluate the effect of iC3b on monocyte IL-12 production,
purified monocytes were incubated with medium alone, EA, or EAiC3b in
combination with SAC (0.001%) as a stimulator for IL-12 for 20 h
(IL-12 was not detectable in resting monocytes without any
stimulation). Total monocyte RNA was then extracted, and RT-PCR was
performed for IL-12 p40. Although IL-12 p40 mRNA was not detectable
when monocytes were incubated with medium alone, incubation with SAC
briskly stimulated IL-12 mRNA synthesis (Fig. 5A, lanes 1 and
2). This induction of IL-12 was down-regulated when
incubated with EAiC3b (Fig. 5A, lane 4), but not
with EA (Fig. 5A, lane 3). ELISA analysis of
protein secretion into the supernatant under identical conditions
confirmed that reduced mRNA production by iC3b resulted in
significantly reduced IL-12 p70 formation (Fig. 5B). As with
mRNA for IL-12 p40, the production of IL-12 p70 was not detected in
medium alone, but was up-regulated when incubated with SAC. This
production was significantly inhibited by incubation with EAiC3b
compared with medium or EA in combination with SAC (Fig. 5B;
p < 0.01; n = 6).
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regulates IL-12 as well as IL-10 in this
model, TNF- was used to stimulate monocytes in combination with SAC.
However, addition of TNF- did not modify IL-12 mRNA synthesis (data
not shown), and protein secretion was not significantly altered,
although it was slightly decreased by TNF- (Table II).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. This system models
the UV-influenced cutaneous microenvironment having similar cytokine
and iC3b patterns in combination with monocyte infiltration. We have
previously shown that CD11b+ Mo/Mph infiltrate UV-exposed
skin (15, 16), and that they are implicated in UV-induced
immunosuppression and tolerance induction (17, 18, 19). Furthermore,
depletion of iC3b (a ligand for CD11b) or blockade of CD11b itself in
UV-exposed skin is capable of negating these effects of UV in mice (18, 24). In addition, our previous findings indicate that
CD11b+ Mo/Mph are the main source of IL-10-secreted protein
in UV-exposed human skin compared with keratinocytes (20, 21).
Conversely, Langerhans cells, which produce IL-12 (41), are depleted in
the epidermis after UV irradiation, as are their dendritic
Ag-presenting counterparts in the dermis (42, 43, 44). This is associated
with loss of IL-12-producing cells in human dermis after UV (21).
Restoration of immune-sensitizing potential after UV occurs when rIL-12
is provided (13, 14), as occurs with blockade of CD11b and depletion of
iC3b. These observations led to the hypothesis that the ligand for
CD11b may be induced in UV-irradiated skin and that signaling through
ß2 integrin is partially responsible for the regulation
of cytokine production (both IL-10 and IL-12) by Mo/Mph.
We performed immunofluorescence studies to determine whether iC3b
deposits are present in UV-exposed human skin. As hypothesized,
UV-exposed skin clearly showed increased iC3b deposits at the DEJ
relative to normal skin; iC3b+ keratinocytes in the
epidermis also appeared (Fig. 1). Moreover, double staining revealed
that infiltrating CD11b+ Mo/Mph appeared to be juxtaposed
to these deposits at the DEJ before they migrated into the epidermis
where they were also found adjacent to iC3b+ keratinocytes
(Fig. 2). These data suggested that a major ligand for CD11b, iC3b, was
abundant in UV-irradiated human skin.
Another key element implicated in UV-induced immunosuppression is
TNF-. (32, 33). It is well known that TNF- is produced in
UV-exposed skin by keratinocytes and mast cells (34, 35). TNF- has
also been reported to induce monocyte IL-10 (36). However, the in vivo
localization of TNF- mRNA in UV-exposed human skin has not been
explored, and it is not clear whether TNF- might be influencing
blood monocytic cells as they enter, migrate, and differentiate in the
dermis after UV injury. We performed in situ hybridization for TNF-
and found that TNF- mRNA was indeed present in the papillary dermis
and basal epidermis in UV-exposed skin (Fig. 3), indicating that
TNF- was being produced in the same microanatomic area that
contained iC3b deposits and infiltrating CD11b+ Mo/Mph.
To address how binding of iC3b to ß2 integrin alters
cytokine production in the presence of TNF-, we used resting
monocytes from peripheral blood rather than human skin tissue in our
experimental model, because tissue Mo/Mph have presumably already been
activated by many factors in skin. After the purification of monocytes,
monocytes were incubated with iC3b. The data clearly demonstrate the
novel finding that iC3b induces IL-10 mRNA and protein. In addition,
IL-10 induction was markedly enhanced by contextual exposure to TNF-
(Fig. 4). To prove more definitively that IL-10 production is due to
the interaction between iC3b and CD11b, CD11b on monocytes was blocked
by M1/70 Ab. This abrogated IL-10 production by EAiC3b, indicating that
iC3b binding to CD11b plays an important role in cytokine production
(Table I). By contrast, the reciprocal immunomodulatory cytokine,
IL-12, was inhibited at the mRNA and protein levels by iC3b (Fig. 5),
confirming the ability of iC3b to inhibit IL-12 (30, 31). Concomitant
TNF- exposure did not prevent inhibition of IL-12. Thus, at the same
time that iC3b induces IL-10 in freshly immigrated monocytes, it may
restrain IL-12 production in vivo.
Although it is not entirely clear how UV exposure induces
immunosuppression, most of the evidence suggests that decreased IL-12
(12, 13, 14), increased IL-10 (3, 4, 5, 6, 7, 8, 9, 10) and TNF- (32, 33) produced by UV
exposure have an important role. Our findings now provide a novel model
of how UV irradiation preferentially induces inflammatory injury and
immunosuppression. Following UV exposure in vivo, there is created in
skin a sequentially evolving milieu of soluble signals, such as iC3b
and TNF-, which drives newly immigrating Mo/Mph toward
IL-10high/IL-12low differentiation.
Therefore, at the time of Ag presentation, Mo/Mph-derived IL-10 in
an IL-12-inhibited environment may modulate APC function so that
proliferation of T cells that mediate immune response is inhibited,
contributing to UV-induced immunosuppression.
Our results differ from recently published work that showed that CR3
signaling had little effect on IL-10 production by monocytes (30, 31).
This may be because we measured induction of IL-10 after stimulation by
iC3b itself, rather than concomitantly with LPS, LPS plus IFN-, or
SAC plus IFN-, which may drown out the effect of iC3b. Our model may
reflect more reliably the in vivo conditions that we believe to be
induced in the UV milieu.
In conclusion, our studies demonstrate a novel mechanism of IL-10
up-regulation and IL-12 down-regulation via iC3b in combination with
TNF-, which may be responsible for Mo/Mph differentiation and
activation as they infiltrate UV-exposed skin and may be relevant to
immunosuppression following UV exposure.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Kefei Kang, Department of Dermatology, Case Western Reserve University and University Hospitals of Cleveland, 11100 Euclid Ave., Cleveland, OH 44106. E-mail address:
3 Abbreviations used in this paper: Mo/Mph, monocytic/macrophagic cells; DEJ, dermal-epidermal junction; EA, immunoglobulin M-coated sheep erythrocytes; EAiC3b, immunoglobulin M- plus iC3b-coated sheep erythrocytes; SAC, Staphylococcus aureus cells.
Received for publication April 17, 1998. Accepted for publication July 23, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and interleukin-10 inhibit antigen presentation by Langerhans cells for T helper type 1 cells by suppressing their CD80 (B7-1) expression. Eur. J. Immunol. 26:648.
-production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells. J. Exp. Med. 178:1041. and ultraviolet B light have similar effects on contact hypersensitivity in mice. Reg. Immunol. 3:139.[Medline]
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: evidence for synthesis and release upon stimulation with endotoxin or ultraviolet light. J. Exp. Med. 172:1609.. Immunol. Cell Biol. 73:226.[Medline]
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