Interleukin-4 and transforming growth factor beta have opposing regulatory effects on gamma interferon-mediated inhibition of Cryptosporidium parvum reproduction.
It was shown previously that enterocytes activated by gamma interferon (IFN-gamma) are efficient effector cells in the killing of Cryptosporidium parvum. How this function is regulated is not clearly understood, but transforming growth factor beta (TGF-beta) and the Th2 regulatory cytokines may play a role. Using an in vitro cell culture system, we investigated how the key regulatory cytokines interleukin-4 (IL-4), IL-10, IL-13, and TGF-beta might modulate the effect of IFN-gamma in inducing resistance to infection in enterocyte cell lines. The results showed that TGF-beta can abolish the inhibitory effect on C. parvum development and that neither IL-13 nor IL-10 influenced the action of IFN-gamma. In contrast, IL-4 cooperated with low concentrations of IFN-gamma (1 and 10 U/ml) to enhance parasite killing. One mechanism that appeared to be involved in the combined activity of IFN-gamma and IL-4 was intracellular Fe(2+) deprivation, but induction of nitric oxide production was not involved. In one cell line, the extents and durations of phosphorylation of STAT1, a transcription factor involved in IFN-gamma signaling, were similar when cells were stimulated with IFN-gamma alone and with IFN-gamma and IL-4 gamma, suggesting that the cooperative effect of the cytokines was not related to STAT1 activation. The effects of the presence of TGF-beta and IL-4 on IFN-gamma function did not appear to involve any alteration in the level of expression of IFN-gamma receptors.
Lean
I-Sarah
IS
Department of Adult and Paediatric Gastroenterology, Barts, and the London School of Medicine, London, United Kingdom.
McDonald
Stuart A C
SA
Bajaj-Elliott
Mona
M
Pollok
Richard C G
RC
Farthing
Michael J G
MJ
McDonald
Vincent
V
D000818:Animals; D018938:Caco-2 Cells; D002460:Cell Line; D016785:Cryptosporidium parvum / Q000187:drug effects / Q000276:immunology* / Q000472:pathogenicity* / Q000502:physiology; D020895:Enterocytes / Q000187:drug effects / Q000276:immunology / Q000469:parasitology; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology*; D016753:Interleukin-10 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology*; D007501:Iron / Q000378:metabolism; D051379:Mice; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D017471:Receptors, Interferon / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D000096743:Interferon gamma Receptor
D007371:Interferon-gamma; D016753:Interleukin-10; D015847:Interleukin-4; D007501:Iron; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D017471:Receptors, Interferon; D016212:Transforming Growth Factor beta; D000096743:Interferon gamma Receptor; C496319:NOS2 protein, human; C496317:Nos2 protein, mouse