ENTAMOEBA-HISTOLYTICA TROPHOZOITES INDUCE AN INFLAMMATORY CYTOKINE RESPONSE BY CULTURED HUMAN-CELLS THROUGH THE PARACRINE ACTION OF CYTOLYTICALLY RELEASED INTERLEUKIN-1-ALPHA

Infection with the protozoan parasite Entamoeba histolytica results in a high mortality worldwide, To initiate infection, E. histolytica tro phozoites in the bowel lumen penetrate the epithelium, and cause exten sive lysis of host cells, The acute amebic lesions in animal models ar e characterized by infiltration with inflammatory cells, particularly neutrophils. The acute host response is likely important for determini ng whether the infection will spread systemically, but little is known regarding the signals which initiate an acute inflammatory response t o E. histolytica, In the studies reported herein, we used an in vitro model system to define the proinflammatory signals produced by epithel ial and other host cells in response to infection with E. histolytica trophozoites. Coculture of human epithelial and stromal cells and cell lines with trophozoites is shown to increase expression and secretion of an array of chemoattractant and proinflammatory cytokines, includi ng IL-8, GRO alpha, GM-CSF, IL-1 alpha, and IL-6. Moreover, high-level secretion of those cytokines is regulated by the paracrine action of cytolytically released IL-1 alpha. A second mechanism for trophozoite- induced IL-8 production involves trophozoite-target cell contact via a galactose-inhibitable amebic adherence protein, and appears to be med iated through increased intracellular calcium levels, These studies de fine novel mechanisms through which acute inflammation can be initiate d in the host in response to a cytolytic pathogen, such as E. histolyt ica.