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‐α), 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‐α, 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‐α receptors, as determined by ligand binding and immunodetection, and did not induce KC TNF‐α production. The KC histamine receptor was also characterized and found not to be influenced by TNF‐α, cis‐UCA, all‐trans‐UCA, or diphenyhydramine (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‐α inducible ICAM‐1 mRNA and cell surface protein expression, 3) this augmentation does not directly involve changes in KC TNF‐α receptor number, affinity, or TNF‐α 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. © 1993 Wiley‐Liss, Inc.