IL-4 and IL-13 downregulate rolling adhesion of leukocytes to IL-1 or TNF-alpha-activated endothelial cells by limiting the interval of E-selectin expression.
Leukocyte extravasation is governed by the endothelium, expressing a defined pattern of adhesion molecules in response to inflammatory stimuli. Among them, E-selectin, which is expressed in response to interleukin 1 (IL-1) or tumour necrosis factor alpha (TNF-alpha), provides rolling adhesion of the circulating leukocytes, a transient and reversible interaction that initiates leukocyte extravasation. In our experiments, E-selectin expression culminated after 4 to 6 h and declined thereafter. After 24 h a considerable amount of E-selectin was presented, reflecting its continuous expression in different inflammatory skin disorders. After preincubation of the endothelial cells with TNF-alpha together with IL-4 or IL-13, E-selectin mRNA transcription and protein expression were markedly reduced at 8 h and almost abolished at 20 h. In contrast, early E-selectin expression between 2 to 6 h was not significantly impaired. In a rotating adherence assay that mimics physiological shear forces in circulation, preincubation of the endothelial cells with TNF-alpha for 4 and 20 h induced similar adherence of neutrophils, which was largely E-selectin dependent. According to the modified expression kinetics of E-selectin in the presence of IL-4 of IL-13 rolling adhesion was unimpaired at 4 h but significantly diminished after 20 h of preincubation. Similar results were obtained with clones of the cutaneous T cell lymphoma cell line HUT78 highly expressing the E-selectin ligand cutaneous lymphocyte-associated Ag. Together, these data suggest that IL-4 and IL-13 control the rolling adhesion by limiting the period of the induced E-selectin expression and may thereby confine the acute phase of leukocyte emigration.