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Am J Physiol Gastrointest Liver Physiol 277: G599-G608, 1999;
0193-1857/99 $5.00
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Vol. 277, Issue 3, G599-G608, September 1999

Cryptosporidium parvum induces apoptosis in biliary epithelia by a Fas/Fas ligand-dependent mechanism

Xian-Ming Chen1, Gregory J. Gores1, Carlos V. Paya2, and Nicholas F. LaRusso1

1 Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, and 2 Division of Experimental Pathology, Mayo Medical School, Clinic and Foundation, Rochester, Minnesota 55905

Although the clinical features of sclerosing cholangitis from opportunistic infections of the biliary tree in patients with acquired immunodeficiency syndrome (AIDS) are well known, the mechanisms by which associated pathogens, such as Cryptosporidium parvum, cause disease are obscure. Using an in vitro model of biliary cryptosporidiosis, we observed that C. parvum induces apoptosis in cultured human biliary epithelia. Both caspase protease inhibitors and neutralizing antibodies to either Fas receptor (Fas) and Fas ligand (FasL) inhibited this process; neutralizing antibodies to other apoptotic cytokines [interleukin-1beta (IL-1beta ), tumor necrosis factor-alpha (TNF-alpha ), and transforming growth factor-beta (TGF-beta )] had no effect. C. parvum stimulated FasL membrane surface translocation, increased both FasL and Fas protein expression in infected biliary epithelia, and induced a marked increase of soluble FasL (but not IL-1beta , TNF-alpha , and TGF-beta ) in supernatants from infected cells. When a coculture model is used in which infected and uninfected cell populations were physically separated by a semipermeable membrane, both uninfected biliary epithelia and uninfected Fas-sensitive Jurkat cells (but not a Fas-resistant Jurkat cell line) underwent apoptosis when cocultured with infected biliary epithelia. Moreover, both a neutralizing antibody to FasL and a metalloprotease inhibitor blocked the apoptosis in uninfected cocultured cells. Activation of caspase activity was also observed in uninfected cocultured biliary epithelia. The data suggest that C. parvum induces apoptosis in biliary epithelia by a Fas/FasL-dependent mechanism involving both autocrine and paracrine pathways. These observations may be relevant to both the pathogenesis and therapy of the cholangitis seen in AIDS patients with biliary cryptosporidiosis.

acquired immunodeficiency syndrome; cholangiopathies; opportunistic infections; parasitic diseases; caspase


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