ABSTRACT
Tumor necrosis factor (TNF-alpha) significantly reduced Cryptosporidium parvum development in a murine enterocyte cell line, and a key mechanism of action appeared to be inhibition of parasite invasion. However, TNF-alpha-deficient mice controlled infection as effectively as wild-type mice. This suggests that TNF-alpha might have only a redundant role for establishing immunity against C. parvum.
Subject(s)
Cryptosporidiosis/immunology , Cryptosporidium parvum/immunology , Enterocytes/immunology , Tumor Necrosis Factor-alpha/physiology , Animals , Cell Line , Disease Models, Animal , Immunity, Innate , Mice , Mice, Knockout , Tumor Necrosis Factor-alpha/deficiency , Tumor Necrosis Factor-alpha/geneticsABSTRACT
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.
