Genetic evidence for Lyn as a negative regulator of IL-4 signaling. |
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Authors: | M L Janas P Hodgkin M Hibbs D Tarlinton |
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Institution: | The Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Victoria, Australia. |
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Abstract: | IL-4 has multiple effects on B lymphocytes, many of which are concentration dependent. This is particularly so for Ig isotype switching, where different thresholds of IL-4 stimulation are needed to induce switching from IgM to either IgG1 or IgE. In this report we describe a critical role for the tyrosine kinase Lyn in setting IL-4 signaling thresholds in mouse B lymphocytes. Upon CD40 ligand stimulation of lyn-/- B cells, 10-fold less IL-4 was required to induce switching from IgM to IgG1 and IgE and an increased proportion of B cells isotype switched at each IL-4 concentration. These in vitro results correlate with the in vivo findings that in lyn-/- mice, IgG1 Ab-forming cells develop prematurely in ontogeny and that adult lyn-/- mice have an abnormally high proportion of IgG1-expressing B cells in their spleens. Adult lyn-/- mice also have significantly higher levels of IgE in their serum. These results identify Lyn as a molecule involved in modulating the IL-4 signal in B cells and provide insights into its regulation and how a B cell signaling imbalance may contribute to atopy. |
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