Differential Suppression of the Human Mixed Epidermal Cell Lymphocyte Reaction (MECLR) and Mixed Lymphocyte Reaction (MLR) by Cis‐Urocanic Acid

Abstract

Cis-urocanic acid (UCA), formed in the stratum corneum by UV irradiation of trans-UCA has been proposed as a mediator of UV-induced immunosuppression in the skin. In this study, we examined the in vitro effect of cis-UCA (6-100 micrograms/mL) on the human mixed lymphocyte reaction (MLR) and the mixed epidermal cell lymphocyte reaction (MECLR). Addition of cis-UCA (purified or in a mixture with trans-UCA) did not affect the MLR but was able to induce a 20% suppression of the MECLR responses. Because this effect of cis-UCA on the MECLR was not as strong as could be expected from previous in vivo results, we designed a set of experiments in order to enhance the in vitro immunosuppressive capacity of cis-UCA. Firstly, we preincubated epidermal cells with UCA (50 micrograms/mL). for 3 or 6 days before culture in the MECLR because in vivo repeated UV exposure can lead to a photostationary state, where cis-UCA may be present for several weeks. This pretreatment with cis-UCA resulted in a maximal decrease of the MECLR response of 27%, whereas trans-UCA had no effect. Secondly, we investigated whether UVB irradiation of epidermal cells could make cells more sensitive to cis-UCA. However, addition of trans- or cis-UCA did not potentiate the reduced alloactivating capacity of UVB-irradiated cells. Finally, we examined the possibility of a synergistic effect of cis-UCA with histamine. Addition of histamine suppressed the MLR and MECLR responses, but neither cis- nor trans-UCA were able to modulate this decrease. We conclude that cis-UCA can partly downregulate the human MECLR but not the MLR. The mechanism involved in this differential downregulation is not known. In this respect it is striking that cis-UCA dose not potentiate the UVB- or histamine-induced suppression of the MECLR.

IL-12 Prevents the Inhibitory Effects of cis-Urocanic Acid on Tumor Antigen Presentation by Langerhans Cells: Implications for Photocarcinogenesis

“…These reports are in agreement with the finding that cis-UCA altered vimentin expression among LC, leading to the destruction of their cytoskeleton and reduced APC function (46). Additionally, cis-UCA was able to significantly suppress the mixed epidermal cell lymphocyte reaction, but murine bone marrow-derived dendritic cells exposed to cis-UCA demonstrated only feeble impairment of their allostimulatory capacity (47,48). Although the epidermal cell suspensions we used were enriched for LC, we were not using purified LC.…”

Urocanic Acid Photochemistry and Photobiology

“…The lack of a direct effect on antigen-presenting cells was confirmed in a recent study in which cUA had no effect on either the maturation or function of bone marrow-derived dendritic cells in v i~o (157). The cUA suppressed the mixed epidermal-lymphocyte reaction by a maximum of only 27% following 3-6 day preincubation of human epidermal cells with cUA (158). No effect was seen in another study in which human epidermal cells were incubated for 18 h with cUA (159), and cUA had no effect in a mixed lymphocyte reaction (158).…”

“…The cUA suppressed the mixed epidermal-lymphocyte reaction by a maximum of only 27% following 3-6 day preincubation of human epidermal cells with cUA (158). No effect was seen in another study in which human epidermal cells were incubated for 18 h with cUA (159), and cUA had no effect in a mixed lymphocyte reaction (158). In aggregate, these in vitro studies suggest, but do not prove, that cUA has an indirect, rather than a direct effect on dendritic cells.…”

An Action Spectrum for the Production of cis-Urocanic Acid in Human Skin In Vivo

“…The immunosuppressive properties of UCA in human subjects have not been studied in vivo but in vitro experiments indicate that cis-UCA can suppress natural killer cell activity (Gilmour et al, 1993), suppress antigen presenting function (Hurks et al, 1997), stimulate PGE 2 production by mononuclear cells (Hart et al, 1993) and keratinocytes (Jaksic et al, 1995), and suppress HLA-DR, IL-1b, IL-2, TNFa, and IL-1b production by mononuclear cells (Rasanen et al, 1989;Hart et al, 1993;Laihia et al, 1994).…”