Mitra R S, Shimizu Y, Nickoloff B J
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109-0602.
J Cell Physiol. 1993 Aug;156(2):348-57. doi: 10.1002/jcp.1041560218.
Early cellular and molecular events in inflamed skin include the active participation of epidermal keratinocytes (KCs) and dermal mast cells which can produce diffusible mediators such as tumor necrosis factor-alpha (TNF-alpha), histamine, and urocanic acid (UCA). Rapid induction of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) by KCs is observed following a highly diverse array of stimuli which can provoke both irritant, inflammatory, as well as allergic and immune reactions. To determine if the aforementioned mediators could interact in either an additive or synergistic fashion with each other, cultured KCs were exposed to these mediators alone and in combination, and the degree of ICAM-1 mRNA and protein quantitated. Whereas histamine or cis-UCA alone only weakly induced KC ICAM-1, when they were combined with TNF-alpha, significant augmentation was observed by Northern blot hybridization studies, immunostaining, and FACS analysis. Other histamine derivatives such as L-histidine, 1-methylhistidine, 3-methylhistidine, or all-trans-UCA had no effect. Histamine pretreatment did not affect cell surface high affinity TNF-alpha receptors, as determined by ligand binding and immunodetection, and did not induce KC TNF-alpha production. The KC histamine receptor was also characterized and found not to be influenced by TNF-alpha, cis-UCA, all-trans-UCA, or diphenhydramine (an H1 antagonist), but it was inhibited by cimetidine (an H2 antagonist). These results demonstrate that 1) KCs can be induced to express ICAM-1 by exposure to histamine and cis-UCA, 2) histamine and cis-UCA can also augment TNF-alpha inducible ICAM-1 mRNA and cell surface protein expression, 3) this augmentation does not directly involve changes in KC TNF-alpha receptor number, affinity, or TNF-alpha production and, 4) KCs possess a type 2 histamine receptor which is not the photoreceptor for UCA. These findings highlight the potential for cross-talk between molecules produced by resident cutaneous cell types above (i.e., KCs) and below (i.e., mast cells) the epidermal basement membrane zone. These cells and their mediators can cooperate to respond to either exogenous or endogenous stimuli leading to rapid and strong KC ICAM-1 expression. Such induction of this important adhesion molecule by KCs ensures the retention of T lymphocytes necessary to participate in the maintenance of cutaneous immunohomeostasis.
炎症皮肤中的早期细胞和分子事件包括表皮角质形成细胞（KC）和真皮肥大细胞的积极参与，它们可产生诸如肿瘤坏死因子-α（TNF-α）、组胺和尿刊酸（UCA）等可扩散介质。在一系列高度多样的刺激之后，观察到KC可快速诱导细胞间黏附分子-1（ICAM-1）等黏附分子的表达，这些刺激可引发刺激性、炎症性以及过敏性和免疫反应。为了确定上述介质是否能以相加或协同的方式相互作用，将培养的KC单独或联合暴露于这些介质，并对ICAM-1 mRNA和蛋白的水平进行定量。单独的组胺或顺式-UCA仅微弱诱导KC的ICAM-1表达，但当它们与TNF-α联合时，通过Northern印迹杂交研究、免疫染色和流式细胞术分析观察到显著增强。其他组胺衍生物如L-组氨酸、1-甲基组氨酸、3-甲基组氨酸或全反式-UCA则无作用。通过配体结合和免疫检测确定，组胺预处理不影响细胞表面高亲和力TNF-α受体，也不诱导KC产生TNF-α。对KC组胺受体也进行了表征，发现其不受TNF-α、顺式-UCA、全反式-UCA或苯海拉明（一种H1拮抗剂）的影响，但受西咪替丁（一种H2拮抗剂）抑制。这些结果表明：1）KC暴露于组胺和顺式-UCA可被诱导表达ICAM-1；2）组胺和顺式-UCA还可增强TNF-α诱导的ICAM-1 mRNA和细胞表面蛋白表达；3）这种增强并不直接涉及KC的TNF-α受体数量、亲和力或TNF-α产生的变化；4）KC具有2型组胺受体，它不是UCA的光感受器。这些发现突出了表皮基底膜带上方（即KC）和下方（即肥大细胞）的常驻皮肤细胞类型产生的分子之间存在相互作用的可能性。这些细胞及其介质可以协同对外源性或内源性刺激作出反应，导致KC快速且强烈地表达ICAM-1。KC对这种重要黏附分子的诱导确保了参与维持皮肤免疫稳态所需的T淋巴细胞的滞留。
