Interferon gamma induces enterocyte resistance against infection by the intracellular pathogen Cryptosporidium parvum.
OBJECTIVE
Interferon (IFN)-gamma plays an important role in the immunologic control of infection by the protozoan enteropathogen Cryptosporidium parvum. We tested the hypothesis that IFN-gamma may directly inhibit infection of enterocytes by this pathogen.


METHODS
HT-29, Caco-2, and H4 human enterocyte cell lines were grown in monolayers and incubated with IFN-gamma before exposure with C. parvum. IFN-gamma receptor expression in the cell lines was determined by Western blot analysis.


RESULTS
IFN-gamma inhibited C. parvum infection of both HT-29 and Caco-2 cells but not H4 cells. Response to IFN-gamma was related to the expression of the IFN-gamma receptor in the respective cell lines. The effect of IFN-gamma was partially reversed by inhibition of the JAK/STAT signaling pathway. IFN-gamma mediated its action by at least 2 mechanisms: (1) inhibition of parasite invasion and (2) by modification of intracellular Fe(2+) concentration. No role for tryptophan starvation or nitric oxide synthase activity was found. TNF-alpha and IL-1beta also had anti-C. parvum activity but had no synergistic effect with IFN-gamma.


CONCLUSIONS
IFN-gamma directly induces enterocyte resistance against C. parvum infection; this observation may have important consequences for our understanding of the mucosal immune response to invasive pathogens.
Pollok
R C
RC
Digestive Diseases Research Centre, St. Bartholomew's and The Royal London School of Medicine and Dentistry, London, England. r.c.pollok@mds.qmw.ac.uk
Farthing
M J
MJ
Bajaj-Elliott
M
M
Sanderson
I R
IR
McDonald
V
V
D000818:Animals; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology*; D018938:Caco-2 Cells; D003457:Cryptosporidiosis / Q000188:drug therapy* / Q000276:immunology; D016785:Cryptosporidium parvum / Q000254:growth & development / Q000276:immunology*; D004357:Drug Synergism; D020895:Enterocytes / Q000166:cytology / Q000201:enzymology / Q000469:parasitology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019073:HT29 Cells; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology*; D007375:Interleukin-1 / Q000276:immunology / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology / Q000469:parasitology*; D007501:Iron / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D017471:Receptors, Interferon / Q000096:biosynthesis; D014364:Tryptophan / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology; D000096743:Interferon gamma Receptor
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007371:Interferon-gamma; D007375:Interleukin-1; D007501:Iron; D019001:Nitric Oxide Synthase; D019335:Nitroarginine; D017471:Receptors, Interferon; D014364:Tryptophan; D014409:Tumor Necrosis Factor-alpha; D019323:omega-N-Methylarginine; D000096743:Interferon gamma Receptor