HISTAMINE AND CIS-UROCANIC ACID AUGMENT TUMOR-NECROSIS-FACTOR-ALPHA MEDIATED INDUCTION OF KERATINOCYTE INTERCELLULAR-ADHESION MOLECULE-1 EXPRESSION

Early cellular and molecular events in inflamed skin include the activ e 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 whi ch can provoke both irritant, inflammatory, as well as allergic and im mune reactions. To determine if the aforementioned mediators could int eract in either an additive or synergistic fashion with each other, cu ltured KCs were exposed to these mediators alone and in combination, a nd the degree of ICAM-1 mRNA and protein quantitated. Whereas histamin e or cis-UCA alone only weakly induced KC ICAM-1, when they were combi ned with TNF-alpha, significant augmentation was observed by Northern blot hybridization studies, immunostaining, and FACS analysis. Other h istamine derivatives such as L-histidine, 1-methylhistidine, 3-methylh istidine, or all-trans-UCA had no effect. Histamine pretreatment did n ot affect cell surface high affinity TNF-alpha receptors, as determine d by ligand binding and immunodetection, and did not induce KC TNF-alp ha production. The KC histamine receptor was also characterized and fo und not to be influenced by TNF-alpha, cis-UCA, all-trans-UCA, or diph enyhydramine (an H-1 antagonist), but it was inhibited by cimetidine ( an H-2 antagonist). These results demonstrate that 1) KCs can be induc ed to express ICAM-1 by exposure to histamine and cis-UCA, 2) histamin e and cis-UCA can also augment TNF-alpha inducible ICAM-1 mRNA and cel l surface protein expression, 3) this augmentation does not directly i nvolve changes in KC TNF-alpha receptor number, affinity, or TNF-alpha production and, 4) KCs possess a type 2 histamine receptor which is n ot the photoreceptor for UCA. These findings highlight the potential f or cross-talk between molecules produced by resident cutaneous cell ty pes above (i.e., KCs) and below (i.e., mast cells) the epidermal basem ent membrane zone. These cells and their mediators can cooperate to re spond to either exogenous or endogenous stimuli leading to rapid and s trong KC ICAM-1 expression. Such induction of this important adhesion molecule by KCs ensures the retention of T lymphocytes necessary to pa rticipate in the maintenance of cutaneous immunohomeostasis. (C) 1993 Wiley-Liss, Inc.