Epithelial cells (EC) from various tissues can produce important cytokines and chemokines when stimulated by proinflammatory cytokines. These EC also receive signals from cell surface integrins, like the α3β1 integrin, which is important in cell migration and wound healing of epithelial monolayers. However, little is known of the effect of integrin signals on cytokine responses by EC. Colonic Caco-2 cells treated with an anti-α3 integrin antibody prior to stimulation with the proinflammatory cytokine interleukin (IL)-1 yielded suppressed levels of mRNA and secreted IL-6, IL-8 and monocyte chemoattractant protein-1 as compared to cells treated with normal mouse immunoglobulin G. Lung A549 cells also showed a similar suppression of cytokine secretion. Likewise, treatment of the Caco-2 cells with the same antibody suppressed tumour necrosis factorα-stimulated 1L-6 secretion. Fab fragments of the anti-α3 integrin antibody did not induce the suppressive effect but did block the suppressive effect of the whole antibody suggesting that the effect of the antibody required cross-linking of the integrins. Finally, culture of the Caco-2 cells on laminin type 5 (the major ligand for this integrin) yielded depressed levels of 1L-1-induced IL-6 secretion as compared to cells on laminin type 1. These data are the first indication that the α3β1 integrin may cause a suppression of cytokine responses by EC which may be important in regulating the capacity of EC to respond during inflammation or wound healing.