Diverse repetitive forces deform the intestinal epithelium and basement membrane. Such repetitive deformation induces intestinal epithelial proliferation, differentiation, and intracellular signaling. Although at least some deformation-induced signals probably involve integrins, the matrix-dependence of these signals is poorly understood. We compared rapid strain activation of p38 and jnk in human Caco-2 intestinal epithelial cells cultured on collagen I, collagen IV, laminin, and tissue fibronectin. These signals were inhibited in cells on a fibronectin substrate, but activated by strain on collagens and laminin. Furthermore, adding 300 mug/ml plasma fibronectin (approximately the concentration found in plasma) to the culture medium inhibited strain activation of p38 and jnk in cells cultured on collagen. Since tissue and plasma fibronectin levels vary in acute or chronic inflammatory or infectious conditions, these results suggest that tissue or plasma fibronectin may modulate the intestinal epithelial response to repetitive deformation. (C) 2003 Elsevier Science (USA). All rights reserved.