INVOLVEMENT OF MITOGEN-ACTIVATED PROTEIN-KINASE PATHWAYS IN THE NUCLEAR RESPONSES AND CYTOKINE PRODUCTION INDUCED BY SALMONELLA-TYPHIMURIUMIN CULTURED INTESTINAL EPITHELIAL-CELLS

Central to the pathogenesis of Salmonella typhimurium is its ability t o engage the host cell in a two-way biochemical interaction. As a cons equence of this interaction, a dedicated protein secretion system, ter med type III, is activated in these bacteria and directs-the transloca tion of signaling proteins into the host cell, Secretion of these prot eins stimulates host cell signal transduction pathways that lead to a variety of cellular responses, An important feature of S. typhimurium pathogenesis is the induction of a profound inflammatory response in t he intestinal epithelium. in this report, we show that S. typhimurium induces host cell signal transduction pathways hat lead to the activat ion of the transcription factors NF-kappa B and AP-1, resulting in the production of proinflammatory cytokines such as IL-8, We also show th at S. typhimurium infection of cultured intestinal epithelial cells re sults in the activation of the mitogen-activated protein (MAP) kinases ERK, JNK, and p38, induction of these signaling pathways and the synt hesis of IL-8 was strictly dependent on the function of the invasion-a ssociated type III protein secretion system encoded by S. typhimurium. Pretreatment of cells with the highly specific p38 MAP kinase inhibit or SB 203580 prevented S. typhimurium-induced IL-8 production, These r esults indicate that the inflammatory response induced by S. typhimuri um. may be due to the specific stimulation of MAP kinase signaling pat hways leading to nuclear responses.