Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted State6 gene

Abstract

Signal transducers and activators of transcription (Stats) are activated by tyrosine phosphorylation in response to cytokines, and are thought to mediate many of their functional responses. Stat6 is activated in response to interleukin (IL)-4 and may contribute to various functions including mitogenesis, T-helper cell differentiation and immunoglobulin isotype switching. To evaluate the role of Stat6, we generated Stat6-null mice (Stat6 -/-) by gene disruption in embryonic stem cells. The mice were viable, indicating the lack of a non-redundant function in normal development. Although naive lymphoid cell development was normal, Stat6 -/- mice were deficient in IL-4-mediated functions including Th2 helper T-cell differentiation, expression of cell surface markers, and immunoglobulin class switching to IgE. In contrast, IL-4-mediated proliferation was only partly affected.

The biology of Stat4 and Stat6

“…Indeed, lymphocytes from Stat6-de®cient mice were unable to upregulate MHC Class II, CD23, and IL-4Ra expression in response to IL-4, supporting the importance of Stat6 in the activation of IL-4 inducible genes (Kaplan et al, 1996a;Shimoda et al, 1996;Takeda et al, 1996b). Stat6 de®cient B lymphocytes were also unable to switch to the immunoglobulin isotypes IgG1 and IgE in response to IL-4, a ®nding that correlated with an inability to transcribe the corresponding germline transcripts for these genes (Linehan et al, 1998).…”

“…Changes in gene expression in B cells and macrophages after IL-13 stimulation were also demonstrated to be defective in Stat6-de®cient mice supporting the notion that Stat6 activation is also an important downstream e ector of IL-13 signaling (Takeda et al, 1996a). Stat6-de®cient T helper cells were also unable to di erentiate into Th2 cells in vitro or in vivo, an observation that will be discussed further below (Kaplan et al, 1996a;Shimoda et al, 1996;Takeda et al, 1996b).…”

The role of Stat5a and Stat5b in signaling by IL-2 family cytokines

“…Furthermore, Stat5 proteins can also be activated in COS-7 cells when only the cDNAs encoding for Jak3 and Stat5 are co-transfected . Clearly, Stat6 is a critical signaling molecule that mediates essential actions of IL-4, as demonstrated by the greatly diminished IL-4 function in Stat6 7/7 mice (Kaplan et al, 1996;Shimoda et al, 1996). However, analyses of Stat5 genetargeted mice also indicate that at least Stat5b protein plays an important role in T cell proliferation in response to IL-4 (Imada et al, 1998;Moriggl et al, 1999a).…”

Consequences of Stat6 deletion on Sis/PDGF- and IL-4-induced proliferation and transcriptional activation in murine fibroblasts

“…In Stat6 de®cient mice, IL-4-induced proliferation of T cells as well as B cells after IgM stimulation was dramatically reduced (Kaplan et al, 1996;Shimoda et al, 1996;Takeda et al 1996). Th2 helper T cell di erentiation and immunoglobulin class switching were greatly diminished (Kaplan et al, 1996;Shimoda et al, 1996;Takeda et al, 1996).…”

“…IL-4R activation (Wang et al, 1992) results in tyrosine phosphorylation of many signaling molecules including Jak1, Jak3 (Johnston et al, 1994;Witthuhn et al, 1994), IRS-1 (Wang et al, 1993b), IRS-2/4PS (Wang et al, 1993a), and Stat6 (Hou et al, 1994;Kotanides and Reich, 1993;Quelle et al, 1995;Schindler and Darnell, 1995). In Stat6 de®cient mice, IL-4-induced proliferation of T cells as well as B cells after IgM stimulation was dramatically reduced (Kaplan et al, 1996;Shimoda et al, 1996;Takeda et al 1996). Th2 helper T cell di erentiation and immunoglobulin class switching were greatly diminished (Kaplan et al, 1996;Shimoda et al, 1996;Takeda et al, 1996).…”