The role of cytokines in ultraviolet-B induced immunosuppression

ARTICLE

INTRODUCTION

The biological effects of ultraviolet B (UVB) radiation have been under extensive investigation for the last two decades, starting with its identification as a carcinogenic agent. There is evidence from epidemiological data that exposure to UVB increases the incidence of non-melanoma skin cancer and, in addition, that it inhibits the cellular immune response to these highly immunogenic tumors, thereby facilitating their outgrowth [1, 2]. Furthermore, it has been demonstrated that UVB suppresses contact hypersensitivity (CHS), delayed type hypersensitivity (DTH) and alloantigen responses [3-5]. This form of unresponsiveness or peripheral tolerance is, at least in part, mediated by "suppressor" T-cells. As a consequence of the observed impairment of cellular immunity, a reduced resistance to infections (such as Herpes simplex, Candida albicans and Mycobacterium bovis) has been observed [6, 7]. These deleterious effects of this environmental factor have stimulated research on the mechanisms underlying the immunosuppressive effect of UVB in which T-cells and the immunomodulatory functions of cytokines appear to play an essential role.

PHOTORECEPTOR

UVB radiation is defined as electromagnetic radiation with a wavelength ranging from 290 to 320 nm, as depicted in Figure 1. The energy load of the photons enables them to penetrate only the epidermis and the upper layers of the dermis. Within these layers the energy is absorbed by photoreceptors and transduced into biological effects. Several candidate molecules have been proposed which absorb UVB light in the skin and may mediate UVB-induced effects on cellular responses; among them DNA and urocanic acid (UCA) have received most attention. UVB irradiation of cellular DNA has been found to generate a large variety of photoproducts (e.g. cyclobutyl pyrimidine dimers and 6-hydroxy-dihydropyrimidine) as well as DNA double-strand breaks. Formation of pyrimidine dimers occurs most frequently [8]. These mutagenic effects might result in the transcriptional upregulation of certain cytokine genes. Indeed, induction of DNA double-strand breaks in murine skin in vivo, by means of liposome encapsulated endonucleases, has been shown to result in enhanced tumor necrosis factor alpha (TNF-alpha) production by epidermal cells [9, 10].

A second candidate photoreceptor for UVB is urocanic acid, a naturally occurring component of the superficial cornifying epidermis [11]. Upon absorption of UVB light, urocanic acid in the stratum corneum isomerizes from its naturally occuring trans configuration to a cis form. Similar to the effect observed following irradiation with UVB, intravenous injection of cis-urocanic acid suppresses the CHS response, a process which is probably mediated by enhanced release of TNF-alpha by keratinocytes [11, 12] (see below).

KERATINOCYTES

Within hours after UVB exposure, keratinocytes are triggered to produce and/or release a plethora of cytokines. These mediators play an important role in local and systemic inflammatory reactions and in the modulation of most immune responses. As shown in Table 1, UVB modulates the transcription of a wide variety of keratinocyte-derived cytokines. Following UVB irradiation, autocrine stimulation of keratinocytes by interleukin (IL)-1alpha results in an enhanced production of IL-1alpha, IL-6 and granulocyte-macrophage-colony stimulating factor (GM-CSF), whereby IL-1alpha, IL-10 and TNF-alpha act in a paracrine manner on Langerhans cells (see below).

In UVB irradiated skin, upregulation of the expression by keratinocytes of IL-8 has been demonstrated [13]. The chemotactic properties of the enhanced expression of chemokines, such as IL-8, RANTES and IFN-gamma inducible protein 10, might contribute to the extensive infiltrates of macrophages and neutrophils that are observed in UVB irradiated skin.

Some of the induced cytokines released upon UVB irradiation (IL-1, IL-6, TNF-alpha and IL-10) have been detected in serum and are thought to mediate suppression of systemic immunity by modulating the antigen-presenting function of splenocytes (see below) [14-17]. Interestingly, upregulation of a 40 kDa protein which inhibits the activity of IL-1 [18], and the IL-1 receptor antagonist in the stratum corneum have been reported as well [19]. These anti-inflammatory factors are antagonists of IL-1 and are considered relevant mediators of immunosuppression in the skin. Recently, it was demonstrated that UVB also affects the expression of IL-1 receptors type I and II (IL-1RI and IL-1RII) on human keratinocytes [20]. It was shown that within 1 hour after UVB exposure IL-1RII was upregulated and returned to background levels within 24 hours, whereas IL-1RI expression initially decreased and later increased. Since IL-1RII probably functions as a scavenger for IL-1, the resulting effect of UVB is an initial unresponsiveness to IL-1 followed by enhanced sensitivity of keratinocytes for IL-1.

The effect of UVB on the expression of intercellular adhesion molecule-1 (ICAM-1) has been studied in detail [21, 22]. ICAM-1 expression is inhibited the first 24 hours after irradiation, followed by upregulation. This biphasic expression is thought be to regulated by the transient expression of IL-1alpha, IL-1RI and IL-RII [20]. Apart from ICAM-1, upregulation of E-selectin on endothelium is observed following UVB irradiation [21]. This effect is thought to be predominantly mediated by TNF-alpha. Upregulation of E-selectin on endothelium is generally considered an important early event in inflammation and is followed by infiltration of neutrophils, and macrophages into UVB injured skin [23]. No effect on the expression of vascular cell adhesion molecule-1 (VCAM-1) has been demonstrated [21].

LANGERHANS CELLS

In addition to direct effects originating from the non-specific release of keratinocyte-derived cytokines, UVB irradiation also induces antigen-specific immunosuppression. In mice exposed to a low dose of UVB, subsequent challenge with a hapten on the same cutaneous site decreases the CHS response as compared to nonirradiated animals, whereas application of a different hapten mounts a normal immune response [3]. This indicates that UVB-induced unresponsiveness is antigen-specific. Mixed leukocyte reactions, performed with UVB irradiated epidermal cells or splenocytes as stimulator cells, are suppressed as well, suggesting impairment of antigen-presenting functions [4]. Indeed, Langerhans cells (LC) have been shown to be both directly and indirectly affected by UVB irradiation. Their morphology changes from a dendritic appearance into cells with a roundish shape, they have lost characteristic markers (e.g. membrane ATPase) and are reduced in numbers in the epidermis following UVB exposure [3]. Recently, a reduction of the expression of vimentin within the cytoplasm of LC was demonstrated in UVB irradiated mice. Circumstantial data indicate that this reduction might correlate with disruption of the cytoskeleton and with impairment of CHS responses [24]. This suggests one mechanism whereby UVB impairs the antigen-presenting capacity of LC. An alternative mechanism might be that UVB affects the expression of MHC II molecules on LC. However, electron microscopical studies showed that UVB did not alter the density of MHC II molecules. Furthermore, UVB irradiated LC were still able to migrate to the draining lymph nodes and present antigen to T-cells. This is not surprising since the observed immunosuppression following local UVB irradiation is antigen-specific implying that the process of antigen-presentation must have taken place. Migration of LC towards lymph nodes is increased following UVB radiation [25], a process in which keratinocyte-derived TNF-alpha is thought to play an essential role.

ROLE OF TNF-alpha

TNF-alpha mediates its effects by binding to two distinct TNF receptors, one of 55 kDa (TNFR-p55) and one of 75 kDa (TNFR-p75). Soluble forms of both receptors (sTNFR) which can be produced by proteolytic cleavage are able to neutralize the effects of TNF-alpha [26]. UVB irradiation initially decreases TNFR-p55 expression by keratinocytes, but later expression is increased [27]. This biphasic modulation of TNFR-p55 expression by keratinocytes affects the ability of these cells to respond to TNF-alpha. Human keratinocytes lack expression of TNFR-p75. Production of sTNFR-p55 by human keratinocytes remains unaffected by UVB irradiation [27].

As already mentioned TNF-alpha plays a crucial role in induction of the immunomodulatory effects of UVB. UVB irradiation evokes morphological changes of LC and impairment of CHS. These effects are mimicked by intradermal injection of a low dose of TNF-alpha. Furthermore, UVB-induced CHS impairment could be reversed by anti-TNF-alpha [28]. This clearly indicates that UVB exposure impairs CHS induction by a mechanism that requires TNF-alpha, which alters the function of LC. At present it is still not known whether or not TNF-alpha is involved in antigen-specific immunosuppression. From studies using TNFR-p55 knock-out mice, it was shown that TNF-alpha plays a regulatory role in CHS, but is not required to induce UVB-induced antigen-specific immunosuppression [29].

Interestingly, different mice strains are not equally susceptible to UVB-induced immunosuppression. In order to obtain 50% suppression of the CHS response, BALB/c mice require nearly six times more UVB than C57BL/6 mice [30]. The susceptibility is assumed to be a genetically determined trait, which is governed by polymorphic alleles at the TNF-alpha and LPS loci. Resistance to the effects of UVB is a recessive trait and can be conferred by homozygosity at either the TNF-alpha or the LPS locus [31]. It has been proposed that polymorphisms in the non-coding sequences at the TNF-alpha locus between UVB-susceptible and resistant mice, results in modulation of the transcription rate of cytokine mRNA or differences in cytokine mRNA stabilization. Consequently, activation of the susceptibility loci in keratinocytes by UVB results in the generation of excessive amounts of intracutaneous TNF-alpha [32].

ANTIGEN PRESENTATION TO T-CELLS

The viability or depletion of LC in the skin does not account for the loss of antigen-presenting function following UVB radiation. It is believed that the interplay between antigen-presenting cells (APC) and T lymphocytes results in the observed antigen-specific unresponsiveness. Following acute low dose UVB irradiation, mice demonstrate antigen-specific suppressor T-cells in the lymph nodes and spleen, which allow adoptive transfer of the specific tolerance to syngenic naive recipients [33]. This could explain the observed systemic effects of UVB.

Tolerance for a specific antigen can be either based on active suppression mediated by regulatory cells, or clonal deletion, or on complete T-cell anergy. Continuous exposure of antigens in the skin might select regulatory cells, like long-term specific memory Th1 cells or suppressive CD8⁺ cells. Clonal deletion is believed to be the result of apoptosis of antigen-specific T-cells, whereas anergy induction is known to result from T-cell receptor occupancy in the absence of costimulatory signals provided by APC (e.g. B7.1 or B7.2).

In addition to the central role of LC in mediating UVB-induced tolerance, it has been suggested that other APC play a role as well. Following UVB irradiation, the epidermis becomes populated with infiltrating CD36⁺ macrophages (in humans) which are able to present antigen to CD4⁺ suppressor/inducer cells and to CD8⁺ suppressor/cytotoxic cells [34]. This subset of macrophages is thought to play a role in UVB-induced suppression of CHS responses. Another subset of APC worth considering in the context of UVB induced tolerance are the Thy-1⁺ dendritic epidermal T-cells (DETC) which normally reside in murine epidermis, but following UVB radiation, can be detected in the lymph nodes. These cells were shown to induce suppressor T-cells thereby inhibiting the CHS response [35].

T-CELL SUBSETS

Based on their cytokine secretion patterns, the CD4⁺ T helper cells can be divided into at least two effector populations: T helper 1 (Th1) and T helper 2 (Th2) cells, based on the selective production of cytokines. The Th1 population produces interleukin (IL)-2, lymphotoxin (LT) and interferon (IFN)-gamma, whereas the Th2 cells produce IL-4, IL-5, IL-6 and IL-10. In addition, T helper 0 (Th0) cells have been identified which secrete both Th1 and Th2 cytokines [36]. Cytokines are involved in the cross-regulation of the different Th subsets. For instance, T-cells incubated in the presence of IL-4 will result in the development of Th2 cells. On the other hand, IL-12 produced by monocytes, macrophages and B cells, is required for the generation of Th1 cells and subsequent IFN-gamma production. Notably, IFN-gamma has a positive feedback effect by enhancing IL-12 production by APC [37]. The production of IL-12 can be negatively regulated by the Th2-derived cytokines IL-4 and IL-10, resulting in decreased stimulation of cytokine production by Th1 cells (IFN-gamma). Interestingly, IL-12 can not inhibit priming for IL-4 production, demonstrating a dominant effect of IL-4 on the phenotype of the induced immune response [38]. Other cytokines, such as IFN-gamma, transforming growth factor (TGF)-ß and IL-10 also affect the cytokine production by CD4⁺ T-cells, but their effects are, in general, less pronounced then that of IL-4 and IL-12. Hence the balance of IL-4 and IL-12 eventually determines the differentiation of Th0 cells into either Th1 or Th2 cells. The existence of distinct positive and negative feedback mechanisms suggest that once a Th1 or Th2 type immune response is established, the response is irreversibly committed to a particular cytokine profile. However, it has been shown in vitro that differentiated Th1 cells can be converted into IL-4 producers by exposure to IL-4, while a Th2 phenotype is generally considered to be not reversible [39].

MODULATION OF CYTOKINE ACTIVITY BY UVB

The hypothesis that UVB alters the LC APC function and consequently promotes the induction of T-cell tolerance was further supported by findings of Simon et al. [40]. They demonstrated that UVB-irradiated, purified LC had lost the ability to present keyhole limpet hemocyanin (KLH) to Th1 cells, whereas the capacity to activate Th2 cells was not altered. The unresponsive Th1 cells were unable to produce IL-2 and to proliferate upon stimulation with non-irradiated APC, but they responded normally when exogenous IL-2 was added. This suggests that UVB exposure results in clonal anergy of Th1 cells, rather than deletion. Splenic adherent cells incubated in vitro with supernatant of UVB-irradiated keratinocytes could mimic the preferential presentation of LC to Th2 cells, whereas prior treatment of the supernatant with anti-IL-10 antibodies resulted in presentation to both Th1 and Th2 cells [41]. Furthermore, IL-10 has been shown to induce long-term clonal anergy of Th1 cells [14, 42]. In vivo, antibodies to IL-10 could block the UVB-induced suppression of DTH responses [43]. In IL-10 gene-targeted mice, no suppression of DTH was observed following UVB irradiation, whereas a normal suppression of the CHS response was demonstrated [44]. This confirms the central role of IL-10 in the UVB-induced inhibition of the DTH, and also shows that the suppression of the DTH and CHS responses are mediated via different pathways. Since IL-10 is able to negatively regulate the production of IL-12 and inhibit the activation of Th1 cells, it may fulfill an important role in skewing the Th population to a Th2 phenotype. Systemically, Th2 derived IL-10 may help to preserve the Th2 bias by inhibiting the activation of Th1 cells. The local secretory source of IL-10 following UVB in the epidermis is still open to question and, in addition, the expression of IL-10 by human keratinocytes is still controversial. Although various research groups have reported the expression and production of IL-10 by these cells [23, 45], a recent report describes that in contrast to their murine counterparts, human keratinocytes lack UVB-induced expression of IL-10 [46]. In the latter case it is likely that not keratinocytes but infiltrating macrophages function as the major source of IL-10 [23].

Since it has been demonstrated that both UVB and IL-10 have no effect on MHC II expression [14], much attention has focussed on the potential modulation of costimulatory signals. Two candidate molecules on the APC are ICAM-1 and B7. ICAM-1 expression on LC has been reported to be reduced following UVB exposure, thereby abrogating the possibility of the APC providing costimulation via this pathway to the T-cell. However, at present no studies have demonstrated that the absence of signal 2 delivered by ICAM-1 leads to anergy of Th1 cells. In contrast, it has been reported that signalling via B7.1 (CD80) preferentially activates Th1 cells, whereas B7.2 (CD86) induces Th2 activation [47]. Whether or not the skewing towards a Th2 phenotype and/or anergy of Th1 cells following UVB irradiation can be explained in terms of B7 usage is still unclear. Freshly isolated LC express no B7.1 and B7.2 is absent or expressed at low levels [48, 49]. Culture of LC upregulates the expression of B7 molecules, whereas UVB irradiation prevents the upregulation of B7.1 and B7.2 [49]. Inhibition of mixed epidermal cell leukocyte responses in this system could be overcome by anti-CD28 antibody, indicating a role for B7 molecules in the UVB-induced suppression of antigen-presenting functions. Whether or not these costimulatory molecules are also responsible for the skewing towards the Th2 phenotype remains to be determined.

IL-12 has also been recognized as a critical mediator in the cross-regulation of Th1 and Th2 responses thereby promoting the preferential activation of Th1 cells. Injection of IL-12 in UVB-irradiated mice restores immune function and overcomes UVB-induced immunosuppression [50]. This observation is in agreement with the proposed mechanism that UVB affects the Th1/Th2 bias, since IL-12 is known to induce the development of Th1 cells (in vitro and in vivo) resulting in high levels of IFN-gamma. One possible explanation for the restoration of the immune response by IL-12 following UVB exposure, might be a blockade in the production of IL-10 or an increase in the release of IFN-gamma. Recently, it has been shown that presentation of UVB-irradiated monocytes to Th1 cells in vitro reduced IFN-gamma and IL-12 production. Addition of IL-12 in this system restored the production of IFN-gamma [51]. Interestingly, it has been reported that one of the effects of IL-12 in vivo is to abrogate the activity of CD8⁺ suppressor cells responsible for the UVB-induced inhibition of CHS responses in mice (T. Schwarz, oral presentation).

CONCLUSION

Current data support the hypothesis that UVB irradiation reverses the preferential activation of LC from Th1 cells to Th2 cells. Consequently, a number of changes are expected to occur. First of all, typical Th1-mediated responses (such as DTH responses) are altered, whereas Th2-mediated responses (such as specific antibody production) are not affected. The preserved proliferative capacity of Th2 cells renders these cells potential mediators of active suppression of Th1-mediated responses and might therefore represent one mechanism of inducing the observed tolerance following UVB irradiation. Notably, Th2-derived IL-10 maintains the suppression of Th1 proliferation and cytokine production, thereby prolonging the state of tolerance.

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