Requirement for TNF-Tnfrsf1 signalling for sclerosing cholangitis in mice chronically infected by Cryptosporidium parvum.

An increase in mRNA levels for TNF and Tnfrsf1 in the bile ducts of Tnfsf5-/-(CD40 ligand or CD154 knockout) mice developing cholangitis following infection by Cryptosporidium parvum (CP) is accompanied by staining for TNFalpha in areas of inflammation. To determine whether TNF contributed to the bile duct damage seen in chronically-infected animals, we bred B6 mice with disrupted genes for Tnfrsf1a, Tnfrsf1b and Tnfsf5. Following CP infection, the Tnfsf5-/- Tnfrsf1a & 1b-/- mice were spared from cholangitis, even though their intestinal and bile duct infection by CP persisted. Mice with disruptions of Tnfsf5, and either Tnfrsf1a or Tnfrsf1b, developed bile duct sclerosis similar to that seen in CD40 and Tnfsf5 knockouts. Our data indicate that signalling through either TNF receptor is sufficient for the bile duct damage that follows chronic CP infection in mice, with disruption of the Tnfsf5 molecule.