Essential role of Stat6 in IL-4 signalling

Abstract

Interleukin-4 (IL-4) is a pleiotropic lymphokine which plays an important role in the immune system. IL-4 activates two distinct signalling pathways through tyrosine phosphorylation of Stat6, a signal transducer and activator of transcription, and of a 170K protein called 4PS. To investigate the functional role of Stat6 in IL-4 signalling, we generated mice deficient in Stat6 by gene targeting. We report here that in the mutant mice, expression of CD23 and major histocompatibility complex (MHC) class II in resting B cells was not enhanced in response to IL-4. IL-4 induced B-cell proliferation costimulated by anti-IgM antibody was abolished. The T-cell proliferative response was also notably reduced. Furthermore, production of Th2 cytokines from T cells as well as IgE and IgG1 responses after nematode infection were profoundly reduced. These findings agreed with those obtained in IL-4 deficient mice or using antibodies to IL-4 and the IL-4 receptor. We conclude that Stat6 plays a central role in exerting IL-4 mediated biological responses.

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).…”

Thymic stromal lymphopoietin is a critical mediator of IL‐13‐driven allergic inflammation

“…Female 4-6-wk-old BALB/c, C57BL/6, WBB6F1-1/1, and mast celldeficient WBB6F1-W/W v mice were purchased from Japan SLC (Tokyo, Japan), Stat6-deficient mice [28] on BALB/c background were provided by Dr. Hiroshi Nakajima (Chiba University, Chiba, Japan), Myd88-deficient mice [29] on C57BL/6 background were purchased from Oriental Yeast (Tokyo, Japan), and these mice were bred under specific pathogen-free conditions. All animal experiments were approved by the Institutional Review Board of the University of Yamanashi.…”

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

“…Previous studies have suggested that Stat6 may play a role in IL-4-induced lymphocyte proliferative responses (Kaplan et al, 1996;Takeda et al, 1996). To investigate the role of Stat6 in PDGF and IL-4-induced ®broblast proliferation, we examined the e ects of IL-4 and PDGF on [ 3 H]thymidine incorporation by wild-type and Stat6 7/7 early passage ®broblasts utilizing a ®broblast proliferation assay.…”

“…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).…”