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Department of Immunology, The University of Texas, M. D. Anderson Cancer Center, Houston, TX 77030
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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secretion, the major signal for
the development of a Th2 response is IL-4. Here we tested the
hypothesis that UV irradiation induces IL-4 secretion. UV irradiation
induced serum IL-4 in a dose-dependent fashion. Injecting UV-irradiated
mice with anti-IL-4 blocked immune suppression. We could find no
evidence, however, supporting secretion of IL-4 by UV-irradiated
keratinocytes. Rather, we suggest that prostaglandins released by
irradiated keratinocytes induce serum IL-4 since treating UV-irradiated
mice with a cyclooxygenase-2 inhibitor blocked its production.
Moreover, we found that treating UV-irradiated mice with anti-IL-4
suppressed serum IL-10 levels. In addition, injecting normal mice with
PGE2 induced serum IL-4 and IL-10. We suggest that UV
exposure activates a cytokine cascade (PGE2 
IL-4
IL-10) that ultimately results in systemic immune suppression. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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One potential mechanism that may explain the suppressive effects of UV
radiation on immune reactions, such as delayed type hypersensitivity
(DTH)2 and tumor
rejection, may be the differential activation of T helper cell subsets.
Data from a number of laboratories have suggested that one consequence
of UV exposure is a shift in the activation of T cells from a Th1 to a
Th2-type immune response. Araneo et al. isolated T cells from mice that
were exposed to UV radiation and immunized with Ag. These cells were
then stimulated with Ag in vitro, and IL-2, IL-4, and IFN-
production was measured. Compared with normal controls, the T cells
from the UV-irradiated mice were found to secrete less IL-2 and
IFN-, but more IL-4, indicative of a shift toward a Th2-like
reaction (8).
The mechanism through which UV irradiation influences the activation of T cell subsets appears to involve alteration of APC function. Simon and colleagues found that, while normal Langerhans cells could present Ag to both Th1 and Th2 clones, direct UV irradiation of the Langerhans cells blocked Ag presentation to the Th1 cells but had no inhibitory effect on presentation to the Th2 cells (9). In addition it was reported that when UV-irradiated Langerhans cells were used as APC, not only were the Th1 cells nonresponsive, they were rendered tolerant to further antigenic stimulation (10). Almost identical data were reported by Enk et al., who examined the effects of IL-10 pretreatment on Langerhans cell function (11). Treatment of Langerhans cells with IL-10, a cytokine released by UV-irradiated keratinocytes (12), blocked Ag presentation to Th1 cells but did not interfere with Ag presentation to Th2 clones. Moreover, similar to direct UV irradiation, IL-10 pretreatment rendered the Th1 cell population tolerant to subsequent antigenic stimulation.
IL-10 has also been implicated as an essential mediator in the induction of systemic immune suppression following UV exposure. IL-10 is found in the serum of UV-irradiated mice (13, 14), and treating UV-irradiated mice with anti-IL-10 blocks the induction of immune suppression (12). UV-induced IL-10 can also alter the activation of Th1 and Th2 cells. When adherent spleen cells from UV-irradiated mice were used to present Ag to Th1 cells, their activation was significantly suppressed. Conversely, Th2 cell function, as measured by cytokine secretion by the responder cells, was significantly enhanced. Administration of monoclonal anti-IL-10 to the UV-irradiated mice that were the source of the APCs reversed these effects and restored the ability of APC from the UV-irradiated mice to present to Th1 cells (15).
Additional findings support the hypothesis that UV irradiation may
preferentially alter the balance between Th1 and Th2 cell activation.
First, the Ag-specific suppressor T cells found in the spleens of
UV-irradiated mice appear to be Th2-like cells because blocking IL-4
and/or IL-10 production by these cells abrogates their suppressive
activity (13). Moreover, Yagi et al. reported that a cloned suppressor
T cell line isolated from UV-irradiated mice secretes IL-4 and IL-10,
but not IFN-, suggesting it is a Th2 cell (16). Second, UV exposure
affects the production of Ig isotypes that are helped by different
subsets of T helper cells. In the mouse, Th1 cells provide the help
necessary for the secretion of IgG2a and 2b, whereas Th2 cells provide
help for IgG1 secretion. UV irradiation was found to suppresses the
production of IgG2a and IgG2b in mice infected with Borrelia
burgdorferi. In addition, a small but significant increase in IgG1
Ab production was seen in response to UV exposure. Administration of
monoclonal anti-IL-10 to the UV-irradiated mice returned the amount
of B. burgdorferi-specific IgG2a and IgG2b to levels
that were indistinguishable from the controls, suggesting that
UV-induced IL-10 is altering the activation of Th1 and Th2 cells in
vivo (17). Finally, injecting UV-irradiated mice with IL-12 reversed
the induction of immune suppression as well as blocked the induction
of, and activity of, the UV-induced suppressor T cells (18). Because
IL-12 is reported to enhance the production of Th1 cells (19) and to
block the activation/differentiation of Th2 cells in vivo (20, 21),
these findings provide further support for the hypothesis that UV
exposure blocks Th1 cell function while allowing Th2 cell stimulation
to proceed.
It is clear, however, that, while IL-10 can influence Th1 cell
activation by altering Ag presentation and suppressing IFN-
secretion (22), the major signal for the development of a Th2 response
is IL-4 (23). Although a number of immune modulatory factors, including
TNF-
, IL-1, IL-6, IL-10, and PGE2 are secreted by
UV-irradiated keratinocytes and some are found in the serum of
UV-irradiated mice (24), it is not known if UV exposure also
up-regulates IL-4 production. Because available evidence supports the
hypothesis that UV exposure shifts the immune response to one
predominated by Th2 cells, and because IL-4 is a critical mediator in
the development of a Th2 immune response, the purposes of the
experiments presented here were to determine whether IL-4 is induced
following UV exposure and to determine whether IL-4 is involved in the
induction of immune suppression following UV exposure.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The spontaneously transformed keratinocyte cell line PAM 212 was obtained from Dr. Stuart Yuspa (National Cancer Institute, Bethesda, MD) and grown in complete MEM as described previously (12). The hybridoma secreting anti-IL-4 (11B11; rat IgG1) was purchased from the American Type Culture Collection (Rockville, MD). The hybridoma secreting anti-IL-10 (JES5-2A5.11, rat IgG1) was kindly provided to us by Dr. Anne O’Garra (DNAX Research Institute, Palo Alto, CA). The hybridoma cells were grown in RPMI 1640 tissue culture medium (Life Technologies, Grand Island, NY) supplemented with 10% newborn calf serum (HyClone Laboratories, Logan, UT). The supernatants were collected, the IgG fraction was enriched by 33% ammonium sulfate precipitation, and IgG was purified by passage over protein A/G agarose columns (Pierce Immunochemicals, Rockford, IL). Protein concentration was determined by use of bicinchoninic acid (BCA protein assay kit, Pierce). Control rat IgG was purchased from Sigma Chemical (St. Louis, MO). The IL-2/IL-4-dependent T cell line HT-2 was purchased from ATCC. PGE2 was purchased from Cayman Chemical (Ann Arbor, MI). The selective cyclooxygenase (COX)-2 inhibitor SC236 was kindly provided by Dr. Peter C. Isakson (G. D. Searle & Co., St. Louis, MO). It was diluted in PBS and injected i.p.
Mice
Specific-pathogen-free female C3H/HeNCr (MTV-) and BALB/cAnNCr mice were obtained from the National Cancer Institute Frederick Cancer Research Facility Animal Production Area (Frederick, MD). The animals were maintained in facilities approved by the Association for Assessment and Accreditation of Laboratory Animal Care International, in accordance with current regulations and standards of the U.S. Department of Agriculture, the Department of Health and Human Services, and National Institutes of Health. All animal procedures were reviewed and approved by the Institutional Animal Care and Use Committee. Within each experiment, all mice were age and sex matched. The mice were 8 to 10 wk old at the start of each experiment.
Radiation sources
A bank of six FS-40 sunlamps (National Biological, Twinsberg, OH) was used to irradiate the mice. These lamps emit a continuous spectrum from 270 to 390 nm, with peak emission at 313 nm; approximately 65% of the irradiation is within the UVB range (280–320 nm) of the solar spectrum. The irradiance of the six bulbs averaged 10 J/m2/s, as measured by an IL-1700 research radiometer, using an SEE 240 UVB detector equipped with an A127 quartz diffuser (International Light, Newburyport, MA). Because of shielding by the cage lids, the incident dose received by the mice was approximately 4.5 J/m2/s. Keratinocyte cultures were irradiated with a single FS-40 bulb as described previously (12). The output of this lamp was 1.43 J/m2/s at a tube-to-target distance of 23 cm.
Determination of cytokine levels
For the most part ELISA assays were used to determine cytokine levels. The capture Abs and biotinylated detecting Abs were purchased from PharMingen (San Diego, CA) and used according to the manufacturer’s instructions (2 µg/ml) in a "sandwich" ELISA procedure. Recombinant cytokines were used to generate standard curves; the concentration of each cytokine was determined using the linear portion of the curve. The background response was determined by replacing the recombinant cytokines with PBS, tissue culture medium, or normal mouse serum. The mean OD(410 nm) and SD of triplicate samples was calculated, and a positive response was defined as one having an OD at least three SDs above background. Generally the limit of detection for IL-4 was between 2 and 10 pg/ml and for IL-10 was 15 to 25 pg/ml. Statistical differences between groups were determined by use of a two-tailed Student t test, with a probability of <0.05 considered significant.
Alternatively IL-4 levels were determined by bioassay. Serum samples (in triplicate) from UV-irradiated or nonirradiated control mice were cultured with 5 x 103 HT-2 cells in 96-well microtiter dishes for 18 to 24 h. Background responses were determined by culturing the cells with medium. A standard curve was generated by culturing the cells with different concentrations of rIL-4 (PharMingen). During the last 6 h of culture, 1 µCi of tritiated thymidine (ICN Radiochemical, Irvine, CA) was added to each well. The radioactivity incorporated by the cells was determined by harvesting the cell lysate onto glass fiber filters followed by liquid scintillation counting. The proliferation of the HT-2 cells cultured with serum from the UV-irradiated mice was reduced to background by adding monoclonal anti-IL-4 (11B11; 10 µg/ml) to the wells. Statistical differences between groups were determined by use of a two-tailed Student t test, with a probability of <0.05 considered significant.
Delayed type hypersensitivity (DTH)
The dorsal hair of the C3H/HeN mice was removed with electric clippers, and the mice were exposed to 15 kJ/m2 of UVB radiation. Control mice were shaved but not exposed to UV. Within 2 to 4 h, the mice were injected (i.p.) with 100 µg of anti-IL-4, anti-IL-10, or rat IgG. Five days later the animals were immunized by injecting 2.5 x 107 BALB/c spleen cells into each flank as described previously (25). Six days later, each hind footpad was measured with an engineer’s micrometer (Swiss Precision Instruments, Los angles, CA), the size recorded, and the animals were challenged by injecting 107 BALB/c spleen cells into each hind footpad. Footpad thickness was measured again 18 to 24 h later and the swelling determined. The specific footpad swelling was calculated by subtracting the response found in control mice that were not immunized but were challenged from the swelling seen in mice that were both immunized and challenged. There were at least five mice per group; the data are expressed as specific footpad swelling ± the SD. Statistical differences between the controls and experimental groups were determined by use of a two-tailed Student’s t test, with a probability of <0.05 considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The first series of experiments was designed to determine whether
IL-4 could be found in the serum of UV-irradiated mice. At various
times after UV exposure (15 kJ/m2, a dose of UV that
routinely induces > 50% immune suppression), mice were bled,
serum was obtained, and the IL-4 level was determined by ELISA. Control
samples were simultaneously obtained from mice that were shaved but not
exposed to UV radiation (Fig. 1
).
Although no IL-4 was found in the serum of the shaved nonirradiated
control mice, IL-4 was found in the serum of the UV-irradiated animals
(p < 0.0001; UV vs shaved nonirradiated mice,
Mann-Whitney U test). The peak response was seen 24 h
postirradiation, and by 48 h all the IL-4 was cleared from the
serum.
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). IL-4 was found in the serum of the
UV-irradiated mice, and, as the dose of UV used to irradiate the
animals was increased, higher concentrations of IL-4 were found in the
serum.
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Next we wanted to determine whether the UV-induced serum IL-4
plays any role in the induction of systemic immune suppression. C3H/HeN
mice were exposed to 15 kJ/m2 of UV radiation, and
within 4 h were injected with control rat IgG, anti IL-4, or
anti-IL-10. Five days later the mice were immunized with
alloantigen (BALB/c spleen cells), and the resulting DTH response was
measured 1 wk later. Data from such an experiment are presented in
Table I. Injecting the nonirradiated
control mice with rat IgG, anti-IL-4, or anti-IL-10 had no
effect on the magnitude of the response generated since the DTH
reaction found in these mice was indistinguishable from that observed
in the positive control (p = 0.28 and 0.24,
respectively). UV irradiation, at the dose chosen, caused a significant
suppression of the response (p < 0.0001) and,
as shown previously (12), injecting the mice with anti-IL-10
overcame the induction of immune suppression (p
< 0.0001 UV + anti-IL-10 vs the UV only). Similarly, when the
UV-irradiated mice were injected with anti-IL-4, the induction of
immune suppression was blocked, since the response found in these mice
was significantly different from that found in the UV-irradiated mice
(p < .0001).
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The data reported above indicate that IL-4 plays a critical role
in UV-induced immune suppression. We next wanted to determine the
source of the IL-4. Because skin is the target organ of UV radiation
and most of the energy contained within UV radiation is absorbed within
the epidermis, we tested the hypothesis that keratinocytes are
secreting IL-4 in response to UV irradiation. To accomplish this, we
measured cytokine production by UV-irradiated keratinocytes in vitro.
The spontaneously transformed keratinocyte cell line Pam 212 was
cultured in 100-mm tissue culture dishes and exposed to various doses
of UV radiation. Eighteen to 24 h later, the supernatant fluid was
recovered and the IL-4 content was determined by ELISA. As a positive
control, the IL-10 content of the keratinocyte supernatant was also
measured. Data from this experiment are found in Table II. As expected, UV irradiation of the
keratinocytes resulted in IL-10 secretion, and the amount of IL-10
found in the supernatant fluid increased as the dose of UV used to
irradiate the cells increased. No IL-4, however, was found in the
supernatants of the UV-irradiated keratinocytes, regardless of the dose
of UV radiation applied. Because we found a significant and substantial
decrease in the viability of the keratinocytes when doses higher than
200 J/m2 were used, we did not attempt to determine
whether irradiation with higher doses would result in IL-4 secretion.
This experiment has been repeated three times, and in no case was any
IL-4 found in the supernatant of the UV-irradiated keratinocyte
cell line.
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. As shown previously, IL-4 was not
present in the serum of the normal mice, and injecting SC236 did not
cause IL-4 release into the serum. UV irradiation did cause an
up-regulation of serum IL-4 levels. This UV-induced up-regulation of
serum IL-4 was suppressed by injecting UV-irradiated mice with the
selective COX-2 inhibitor. The suppression was dependent on the dose of
SC236 injected, and complete inhibition of serum IL-4 was found when
0.2 µg of the inhibitor was injected per mouse. These findings
suggest that the IL-4 found in the serum of UV-irradiated mice is
induced by PGE2.
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From the data presented in Table I
, it is clear that
neutralizing either IL-4 or IL-10 blocked UV-induced immune suppression
to an equivalent degree. One potential explanation for this finding is
to suggest that a cascade of events is occurring and that IL-4,
which peaks 24 h after UV exposure (Fig. 1), is acting to
up-regulate the production of serum IL-10, which is found maximally 36
to 48 h post UV (13, 14), and that blocking the activity of either
blocks the induction of immune suppression. To test this hypothesis,
the following experiment was performed. Mice were exposed to UV
radiation (15 kJ/m2) and then immediately injected with rat
IgG or anti-IL-4. Twenty-four to 72 h later the serum from
these mice was collected and serum IL-10 levels were determined. These
data are presented in Table IV. As
demonstrated previously, serum samples from mice exposed to UV and
injected with control IgG were positive for IL-10. Interestingly,
treating the UV-irradiated mice with anti-IL-4 totally blocked the
induction of serum IL-10 (p < 0.05),
suggesting that IL-4 contributes the appearance of IL-10 in the serum
of UV-irradiated mice.
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, injecting
PGE2 into normal mice resulted in the induction of both
IL-4 and IL-10. Thus, these findings suggest that, following UV
exposure, a cascade of events occurs, PGE2 IL-4
IL-10, and that this cascade ultimately results in systemic immune
suppression.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(24). The data presented here
indicate that we can now add IL-4 to the list, since a mAb specific for
IL-4 blocks UV-induced suppression of DTH to alloantigen (Table I).
These findings also illuminate the difficulties in trying to interpret
and integrate all the diverse data published in the literature
concerning the role of UV-induced cytokines in immune suppression. For
example, if we know that IL-4 and IL-10 are both found in the serum of
UV-irradiated mice, and if we neutralize the IL-4 with a specific mAb,
why doesn’t the remaining IL-10 suppress DTH? Similarly, both
PGE2 and IL-10 can be found in the serum of UV-irradiated
mice, so why if we neutralize IL-10 does not the remaining
PGE2 mediate immune suppression? Our data indicate that
these UV-induced immune regulatory factors work in sequence, and not in
parallel, to inhibit inflammatory immune reactions such as DTH. We
suggest that PGE2, which is released by UV-irradiated
keratinocytes (26) and can be found in the serum of UV-irradiated mice
(27), activates a cytokine cascade involving at least IL-4 and IL-10, a
cascade that ultimately suppresses DTH.
Our examination into a potential role for IL-4 in the induction of
immune suppression in UV-irradiated animals was based primarily on
previously published data suggesting that Th2 cells are preferentially
activated following UV-irradiation. Rivas and Ullrich found that the
activity of the UV-induced suppressor T cells was blocked with Abs to
IL-4 and IL-10, suggesting that they are Th2-like cells (13). This was
subsequently confirmed by Yagi et al., who cloned a suppressor cell
from the spleen of a UV-irradiated mouse that upon activation secreted
IL-4 and IL-10, but not IFN- (16). Because IL-4 is the primary
cytokine in driving the differentiation of Th2 cells, we wished to
determine whether UV irradiation induces IL-4. Our data indicate that
IL-4 is found in the serum of UV-irradiated mice and that neutralizing
its biologic activity blocks the induction of immune suppression.
Our focus on PGE2 as the initiator of the cytokine cascade was based on our failure to find any evidence supporting IL-4 secretion by UV-irradiated keratinocytes. This, coupled with the findings of others that PGE2 induces IL-4 (28, 29), and in light of the well known ability of UV to induce PGE2 (26, 27), led us to propose that PGE2 could induce serum IL-4. To examine this question in vivo, we employed the selective COX-2 inhibitor SC236. The advantage in using a selective COX-2 inhibitor to block inducible PGE2 synthesis is a significant reduction in the toxicity (gastric bleeding and kidney damage) usually associated with agents (i.e., indomethacin) that suppress constitutive and inducible prostaglandin production by inhibiting both the COX-1 and COX-2 pathways (30). The complete suppression of serum IL-4 levels in the presence of the COX-2 inhibitor indicates that PGE2 is indeed inducing the serum IL-4 we find in UV-irradiated mice. This finding was supported by the observation that injecting PGE2 into normal mice induces IL-4.
We also noted total ablation of UV-induced serum IL-10 by injecting a mAb to IL-4. Unlike IL-4, there is ample evidence to suggest that both human and mouse keratinocytes secrete IL-10 following UV-irradiation (12, 32, 33, 34). Moreover, the secretion of biologically active IL-10 by keratinocytes is independent of PGE2 secretion since it occurs in the presence of indomethacin (35) and because IL-10 secretion is not inhibited when UV-irradiated keratinocytes are treated with SC236 (data not shown). However, here we demonstrate that serum IL-10 production can be totally suppressed by neutralizing IL-4 activity. We suggest that UV exposure induces IL-10 production at two distinct levels. Direct irradiation of keratinocytes causes the release of epidermal IL-10 (a prostaglandin-independent event), which acts locally to suppress the function of Langerhans cells (11) and to induce tolerance to contact allergens applied directly to UV-irradiated skin (36). The data presented here suggest that keratinocyte-derived IL-10 is not entering into the circulation but rather the IL-10 we find in the serum is induced by a cascade involving at least PGE2 and IL-4. We suggest that the UV-induced, serum-derived IL-10 is mediating the systemic suppression of DTH and impairment of APC function described earlier (12, 15, 17).
The source of the UV-induced serum IL-10, and IL-4 for that matter, is unknown. It is interesting to note, however, that in a study of the mechanism of enhanced sepsis following hemorrhage, Ayala and colleagues found that, when CD4+ T cells from hemorrhagic mice were cultured with PGE2, they secreted IL-10, and the induction of IL-10 by PGE2 could be suppressed by adding monoclonal anti-IL-4 to the cultures (29). Whether peripheral blood CD4+ T cells are producing IL-4 and IL-10 in response to PGE2 in UV-irradiated mice remains to be seen.
Although we focused primarily on PGE2 IL-4 and IL-10 in this study, we need to keep in mind that other mediators induced by UV radiation are undoubtedly involved in the induction of immune suppression. The most prominent is cis-urocanic acid. trans-Urocanic acid is found in the stratum corneum and, upon UV exposure, is isomerized to the immune suppressive cis isomer (37, 38). We believe that cis-urocanic acid may be inducing immune suppression by activating the cytokine cascade described here. Evidence to support this hypothesis comes from a number of studies. First, Hart et al. previously demonstrated that treating human peripheral blood monocytes with cis-urocanic acid induces them to release PGE2 (39). Second, Moodycliffe et al. clearly demonstrated that cis-urocanic acid can be found in the serum of UV-irradiated mice (40), where it can presumably activate monocytes to secrete PGE2. Finally, we showed recently that treating UV-irradiated mice with anti-cis-urocanic acid mAb modulates IL-10 production in vivo (41). We suggest, therefore, that cis-urocanic acid may induce immune suppression by activating the cytokine cascade identified here.
In addition to causing the release of immunosuppressive cytokines, UV-induced PGE2 may also be contributing to immune suppression by blocking the production of essential immune stimulatory cytokines. For example, Tineke et al. have shown that PGE2 is a potent inhibitor of IL-12 production by peripheral blood monocytes (42). Perhaps, in addition to inducing IL-4 and IL-10, PGE2 may also down-regulate IL-12 production by monocytes in the UV-irradiated host. This may explain in part the ability of exogenous IL-12 to reverse the induction of immune suppression following UV irradiation (18, 43).
In summary, we present data indicating that a cascade of events occurs after UV irradiation of the skin that contributes to systemic immune suppression. We suggest that PGE2 released by UV-irradiated keratinocytes induces peripheral blood leukocytes to produce IL-4, which then causes the secretion of IL-10. The UV-induced IL-10 then suppresses systemic APC function and the induction of DTH. This would explain why different experimental approaches, such as blocking prostaglandin production in UV-irradiated mice with indomethacin (27), monoclonal anti-IL-10 treatment (12, 17), and/or injecting monoclonal anti-IL-4 have all been used successfully to abrogate the induction of immune suppression following UV exposure. Furthermore, the findings presented here confirm a very recent observation by El-Ghorr and Norval (44) demonstrating no immune suppression of DTH in UV-irradiated IL-4-deficient mice, and suggest the inability to up-regulate serum IL-4 following PGE2 release as a potential mechanism. We also suggest that cis-urocanic acid, by virtue of its ability to induce blood monocytes to secrete PGE2, may also contribute to this cascade of events.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Stephen E. Ullrich, Department of Immunology-178, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. E-mail address:
3 Abbreviations used in this paper: DTH, delayed type hypersensitivity; COX-2, cyclooxygenase-2.
Received for publication October 14, 1997. Accepted for publication December 19, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. J. Leukoc. Biol. 56:769.[Abstract]
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V. Staniforth, L.-T. Chiu, and N.-S. Yang Caffeic acid suppresses UVB radiation-induced expression of interleukin-10 and activation of mitogen-activated protein kinases in mouse Carcinogenesis, September 1, 2006; 27(9): 1803 - 1811. [Abstract] [Full Text] [PDF]
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 D Wang and R N DuBois PROSTAGLANDINS AND CANCER Gut, January 1, 2006; 55(1): 115 - 122. [Full Text] [PDF]
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 N. Kanda, S. Koike, and S. Watanabe Prostaglandin E2 Enhances Neurotrophin-4 Production via EP3 Receptor in Human Keratinocytes J. Pharmacol. Exp. Ther., November 1, 2005; 315(2): 796 - 804. [Abstract] [Full Text] [PDF]
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S. Gorman, J. W.-Y. Tan, J. A. Thomas, S. L. Townley, P. A. Stumbles, J. J. Finlay-Jones, and P. H. Hart Primary Defect in UVB-Induced Systemic Immunomodulation Does Not Relate to Immature or Functionally Impaired APCs in Regional Lymph Nodes J. Immunol., June 1, 2005; 174(11): 6677 - 6685. [Abstract] [Full Text] [PDF]
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K. Loser, A. Scherer, M. B. W. Krummen, G. Varga, T. Higuchi, T. Schwarz, A. H. Sharpe, S. Grabbe, J. A. Bluestone, and S. Beissert An Important Role of CD80/CD86-CTLA-4 Signaling during Photocarcinogenesis in Mice J. Immunol., May 1, 2005; 174(9): 5298 - 5305. [Abstract] [Full Text] [PDF]
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T. Wachter, M. Averbeck, H. Hara, J. P. Tesmann, J. C. Simon, C. C. Termeer, and R. W. Denfeld Induction of CD4+ T Cell Apoptosis as a Consequence of Impaired Cytoskeletal Rearrangement in UVB-Irradiated Dendritic Cells J. Immunol., July 15, 2003; 171(2): 776 - 782. [Abstract] [Full Text] [PDF]
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A. Sleijffers, B. Yucesoy, M. Kashon, J. Garssen, F. R. De Gruijl, G. J. Boland, J. Van Hattum, M. I. Luster, and H. Van Loveren Cytokine Polymorphisms Play a Role in Susceptibility to Ultraviolet B-Induced Modulation of Immune Responses after Hepatitis B Vaccination J. Immunol., March 15, 2003; 170(6): 3423 - 3428. [Abstract] [Full Text] [PDF]
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M. B. M. Teunissen, G. Piskin, S. d. Nuzzo, R. M. R. Sylva-Steenland, M. A. de Rie, and J. D. Bos Ultraviolet B Radiation Induces a Transient Appearance of IL-4+ Neutrophils, Which Support the Development of Th2 Responses J. Immunol., April 15, 2002; 168(8): 3732 - 3739. [Abstract] [Full Text] [PDF]
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 J. P. Walterscheid, S. E. Ullrich, and D. X. Nghiem Platelet-activating Factor, a Molecular Sensor for Cellular Damage, Activates Systemic Immune Suppression J. Exp. Med., January 14, 2002; 195(2): 171 - 179. [Abstract] [Full Text] [PDF]
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 M de la Torre, R Alcazar, D S. de la Nieta, J Nieto, I Ferreras, and J M Urra Lupus relapse after prostaglandin E1 administration: activation of a cytokine cascade? Ann Rheum Dis, January 1, 2002; 61(1): 91 - 92. [Full Text] [PDF]
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D. W. Mullins, T. N. J. Bullock, T. A. Colella, V. V. Robila, and V. H. Engelhard Immune Responses to the HLA-A*0201-Restricted Epitopes of Tyrosinase and Glycoprotein 100 Enable Control of Melanoma Outgrowth in HLA-A*0201-Transgenic Mice J. Immunol., November 1, 2001; 167(9): 4853 - 4860. [Abstract] [Full Text] [PDF]
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 S. E. Ullrich and H. J. Lyons Mechanisms Involved in the Immunotoxicity Induced by Dermal Application of JP-8 Jet Fuel Toxicol. Sci., December 1, 2000; 58(2): 290 - 298. [Abstract] [Full Text] [PDF]
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A. Boonstra, A. van Oudenaren, B. Barendregt, L. An, P. J. M. Leenen, and H. F. J. Savelkoul UVB irradiation modulates systemic immune responses by affecting cytokine production of antigen-presenting cells Int. Immunol., November 1, 2000; 12(11): 1531 - 1538. [Abstract] [Full Text] [PDF]
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D. A. Schmitt and S. E. Ullrich Exposure to Ultraviolet Radiation Causes Dendritic Cells/Macrophages to Secrete Immune-Suppressive IL-12p40 Homodimers J. Immunol., September 15, 2000; 165(6): 3162 - 3167. [Abstract] [Full Text] [PDF]
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S. Beissert, J. A. Bluestone, I. Mindt, M. Voskort, D. Metze, A. Mehling, T. A. Luger, T. Schwarz, and S. Grabbe Reduced Ultraviolet-Induced Carcinogenesis in Mice with a Functional Disruption in B7-Mediated Costimulation J. Immunol., December 15, 1999; 163(12): 6725 - 6731. [Abstract] [Full Text] [PDF]
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A. P. Pentland, J. W. Schoggins, G. A. Scott, K. N. M. Khan, and R. Han Reduction of UV-induced skin tumors in hairless mice by selective COX-2 inhibition Carcinogenesis, October 1, 1999; 20(10): 1939 - 1944. [Abstract] [Full Text] [PDF]
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P. Moreau, F. Adrian-Cabestre, C. Menier, V. Guiard, L. Gourand, J. Dausset, E. D. Carosella, and P. Paul IL-10 selectively induces HLA-G expression in human trophoblasts and monocytes Int. Immunol., May 1, 1999; 11(5): 803 - 811. [Abstract] [Full Text] [PDF]
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A. M. Moodycliffe, S. Maiti, and S. E. Ullrich Splenic NK1.1-Negative, TCR{alpha}{beta} Intermediate CD4+ T Cells Exist in Naive NK1.1 Allelic Positive and Negative Mice, with the Capacity to Rapidly Secrete Large Amounts of IL-4 and IFN-{gamma} Upon Primary TCR Stimulation J. Immunol., May 1, 1999; 162(9): 5156 - 5163. [Abstract] [Full Text] [PDF]
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) and IL-10 (
) were measured. Each
serum sample was tested in triplicate. The data represent the means and
SEM of serum samples obtained from three individual mice. This
experiment was repeated twice with similar results.