RNA interference (RNAi) is a powerful tool to silence gene expression post-transcriptionally. However, its potential to treat or prevent disease remains unproven. Fas-mediated apoptosis is implicated in a broad spectrum of liver diseases, where inhibiting hepatocyte death is life-saving. We investigated the in vivo silencing effect of small interfering RNA (siRNA) duplexes targeting the gene Fas (also known as Tnfrsf6), encoding the Fas receptor, to protect mice from liver failure and fibrosis in two models of autoimmune hepatitis. Intravenous injection of Fas siRNA specifically reduced Fas mRNA levels and expression of Fas protein in mouse hepatocytes, and the effects persisted without diminution for 10 days. Hepatocytes isolated from mice treated with Fas siRNA were resistant to apoptosis when exposed to Fas-specific antibody or co-cultured with concanavalin A (ConA)-stimulated hepatic mononuclear cells. Treatment with Fas siRNA 2 days before ConA challenge abrogated hepatocyte necrosis and inflammatory infiltration and markedly reduced serum concentrations of transaminases. Administering Fas siRNA beginning one week after initiating weekly ConA injections protected mice from liver fibrosis. In a more fulminant hepatitis induced by injecting agonistic Fas-specific antibody, 82% of mice treated with siRNA that effectively silenced Fas survived for 10 days of observation, whereas all control mice died within 3 days. Silencing Fas expression with RNAi holds therapeutic promise to prevent liver injury by protecting hepatocytes from cytotoxicity.
Helminth exposure appears to protect hosts from inappropriate inflammatory responses such as those causing inflammatory bowel disease. A recently identified, strongly pro-inflammatory limb of the immune response is characterized by T cell IL17 production. Many autoimmune type inflammatory diseases are associated with IL17 release. Because helminths protect from these diseases, we examined IL17 production in helminth-colonized mice. We colonized mice with Heligmosomoides polygyrus, an intestinal helminth, and analyzed IL17 production by lamina propria mononuclear (LPMC) and mesenteric lymph node (MLN) cells. Colonization with H. polygyrus reduces IL17A mRNA by MLN cells and inhibits IL17 production by cultured LPMC and MLN cells. Helminth exposure augments IL4 and IL10 production. Blocking both IL4 and IL10, but not IL10 alone restores IL17 production in vitro. Colonization of colitic IL10-deficient mice with H. polygyrus suppresses LPMC IL17 production and improves colitis. Antibody-mediated blockade of IL17 improves colitis in IL10-deficient mice. Thus, helminth-associated inhibition of IL17 production is likely an important mechanism mediating protection from inappropriate intestinal inflammation.
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