Cryptosporidium parvum activates nuclear factor kappaB in biliary epithelia preventing epithelial cell apoptosis.
OBJECTIVE
Our previous studies have shown that Cryptosporidium parvum induces biliary epithelial cell apoptosis in vivo and causes apoptosis in bystander uninfected biliary epithelia in vitro. We analyzed C. parvum-induced nuclear factor kappa B (NF-kappaB) activation in human biliary epithelial cells and assessed its relevance to epithelial cell apoptosis.


METHODS
In vitro models of cryptosporidial infection using a human biliary epithelial cell line were used to assay C. parvum- induced NF-kappaB activation and associated apoptosis.


RESULTS
Degradation of I(kappa)B and nuclear translocation of the NF-kappaB family of proteins (p65 and p50) were observed in the biliary epithelial cell cultures directly exposed to the parasite. Activation of NF-kappaB was found only in directly infected cells (but not in bystander uninfected cells). A time-dependent secretion of a known NF-kappaB gene product, interleukin 8, from infected cell cultures was detected. C. parvum-induced biliary epithelial cell apoptosis was limited to bystander uninfected cells. In contrast, inhibition of NF-kappaB activation resulted in apoptosis in directly infected cells and significantly enhanced C. parvum-induced apoptosis in bystander uninfected cells.


CONCLUSIONS
These observations support the concept that, while C. parvum triggers host cell apoptosis in bystander uninfected biliary epithelial cells, which may limit spread of the infection, it directly activates the NF-kappaB/I(kappa)B system in infected biliary epithelia thus protecting infected cells from death and facilitating parasite survival and propagation.
Chen
X M
XM
Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic and Foundation, Rochester, Minnesota 55905, USA.
Levine
S A
SA
Splinter
P L
PL
Tietz
P S
PS
Ganong
A L
AL
Jobin
C
C
Gores
G J
GJ
Paya
C V
CV
LaRusso
N F
NF
D000818:Animals; D017209:Apoptosis; D001652:Bile Ducts / Q000378:metabolism / Q000469:parasitology*; D002478:Cells, Cultured; D016785:Cryptosporidium parvum / Q000502:physiology*; D004847:Epithelial Cells / Q000378:metabolism / Q000469:parasitology; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis; D016253:Microscopy, Immunoelectron; D016328:NF-kappa B / Q000378:metabolism*
D016209:Interleukin-8; D016328:NF-kappa B