Krutmann J, Czech W, Parlow F, Trefzer U, Kapp A, Schöpf E, Luger T A
Department of Dermatology, University of Freiburg, F.R.G.
J Invest Dermatol. 1992 Jun;98(6):923-8. doi: 10.1111/1523-1747.ep12460737.
Human keratinocytes (KC) during the course of inflammatory dermatoses strongly express the surface molecule ICAM-1, which plays an important role in the generation of the epidermal inflammatory infiltrate by mediating leukocyte-keratinocyte interactions. Accordingly, KC ICAM-1 expression is known to be induced in vivo and in vitro by cytokines either via the TNF alpha/TNF beta or via the IFN gamma-mediated pathway. In contrast, ultraviolet (UV) radiation previously has been found to potently inhibit cytokine-induced KC ICAM-1 surface expression by a sublethal mechanism. In order to further define this novel immunosuppressive effect of UV light, the effects of in vitro UV radiation on ICAM-1 mRNA expression in transformed human KC (KB cells) were examined. Accordingly, UV light (0-100 J/m2) inhibited IFN gamma- as well as TNF alpha-induced ICAM-1 mRNA expression, if KC were cytokine stimulated immediately after irradiation. After a 12-h incubation period, however, IFN gamma responsiveness was found to be restored in irradiated cells, whereas restoration of responsiveness to TNF alpha required at least a 24-h recovery phase. Moreover, UV light alone did not alter ICAM-1 mRNA levels after 4, 12, or 24 h. After 48 h, however, a significant increase in ICAM-1 mRNA and surface expression in UV-irradiated KC could be observed. In addition, this increase could be superinduced by stimulation of irradiated KC with IFN gamma, but not with TNF alpha. UV-induced upregulation of ICAM-1 expression could be mimicked by stimulating unirradiated cells with supernatants derived from UV-irradiated cells. Addition of biologically active anti-TNF alpha antibodies to UV-irradiated cells or to supernatants derived from UV-irradiated KC, however, did not even partially abolish this ICAM-1-inducing activity. UV light thus seems to affect KC ICAM-1 mRNA expression in a biphasic manner: an early period of inhibition of cytokine-induced ICAM-1 expression is transient and followed by restoration of responsiveness to ICAM-1-inducing cytokines. Moreover, UV itself is able to induce ICAM-1 mRNA expression at this later time point via a TNF alpha-like pathway. These studies identify UV irradiation as a potent modulator of cytokine regulated ICAM-1 gene transcription with the capacity to induce both inhibitory as well as enhancing effects.
在炎症性皮肤病病程中，人角质形成细胞（KC）强烈表达表面分子细胞间黏附分子-1（ICAM-1），该分子通过介导白细胞与角质形成细胞的相互作用，在表皮炎症浸润的形成中发挥重要作用。因此，已知KC的ICAM-1表达在体内和体外可通过细胞因子经由肿瘤坏死因子α/肿瘤坏死因子β或经由干扰素γ介导的途径诱导产生。相比之下，先前已发现紫外线（UV）辐射通过亚致死机制有效抑制细胞因子诱导的KC的ICAM-1表面表达。为了进一步明确UV光这种新的免疫抑制作用，研究了体外UV辐射对转化的人KC（KB细胞）中ICAM-1 mRNA表达的影响。因此，如果KC在照射后立即受到细胞因子刺激，UV光（0 - 100 J/m2）会抑制干扰素γ以及肿瘤坏死因子α诱导的ICAM-1 mRNA表达。然而，经过12小时的孵育期后，发现照射细胞中对干扰素γ的反应性得以恢复，而对肿瘤坏死因子α反应性的恢复至少需要24小时的恢复期。此外，单独的UV光在4、12或24小时后不会改变ICAM-1 mRNA水平。然而，48小时后，可观察到UV照射后的KC中ICAM-1 mRNA和表面表达显著增加。此外，用干扰素γ刺激照射后的KC可使这种增加超诱导，但用肿瘤坏死因子α则不能。用来自UV照射细胞的上清液刺激未照射细胞可模拟UV诱导的ICAM-1表达上调。然而，向UV照射的细胞或来自UV照射的KC的上清液中添加生物活性抗肿瘤坏死因子α抗体，甚至不能部分消除这种诱导ICAM-1的活性。因此，UV光似乎以双相方式影响KC的ICAM-1 mRNA表达：细胞因子诱导的ICAM-1表达的早期抑制是短暂的，随后对诱导ICAM-1的细胞因子的反应性恢复。此外，UV本身能够在这个较晚的时间点通过类似肿瘤坏死因子α的途径诱导ICAM-1 mRNA表达。这些研究确定UV辐射是细胞因子调节的ICAM-1基因转录的有效调节剂，具有诱导抑制和增强作用的能力。
