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and IL-4 by B Cells: Positive and Negative Effects on CD40 Ligand-Induced Proliferation, Survival, and Division-Linked Isotype Switching to IgG1, IgE, and IgG2a1
*
Centenary Institute of Cancer Medicine and Cell Biology, Newtown, Australia;
Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT; and
Medical Foundation, University of Sydney, Sydney, Australia
IL-4 and IFN-
each have potent effects on B cell responses as
well as strong mutual antagonism. Here we have examined the
quantitative effects of these cytokines on CD40 ligand-induced B cell
proliferation, cell survival, and division-linked isotype switching.
Both IL-4 (strongly) and IFN- (weakly) enhanced the number of B
cells found in culture by reducing the average time cells take to enter
the first division cycle and by promoting B cell survival. When added
in combination, the net effect of IL-4 and IFN- on time to division
and survival was a response intermediate between that of the two
cytokines alone, indicating a partial antagonism of IL-4 by IFN-. By
modulating both time to division and cell survival, these small effects
of IFN- are amplified and give rise to large reductions in cell
number in the presence of IL-4. At higher concentrations, IFN- had
minor inhibitory effects on IL-4-induced isotype switching to IgG1 and
greater effects on IgE. A reciprocal relation was observed between the
ability to inhibit IgE at late cell divisions vs induction of IgG2a. In
contrast, IL-4 did not prevent switching to IgG2a induced by IFN-
alone. Therefore, antagonism between IFN- and IL-4 is observed at
multiple levels and over different concentration ranges, resulting in
complex net outcomes. The evolutionary significance of this complexity
is discussed.
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