Stat6 Regulation of In Vivo IL-4 Responses

Finkelman, Fred D.; Morris, Suzanne C.; Orekhova, Tatyana; Mori, Makoto; Donaldson, Debra D.; Reiner, Steven L.; Reilly, Nancy; Schopf, Lisa; Urban, Joseph F.

doi:10.4049/jimmunol.164.5.2303

Cited by 171 publications

(134 citation statements)

References 78 publications

(69 reference statements)

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“…However, there are some reports suggesting that STAT6 can be activated by stimuli other than IL-4 and IL-13, including costimulation by CD28 and IL-2 (22). Although a direct role for STAT6 DNA binding in the IL-4 promoter has been postulated, several studies clearly demonstrate STAT6-independent IL-4 production (21,41). These data suggest that STAT6 activation is not essential for IL-4 transcription, which is consistent with our data showing a divergent effect of NAC on STAT4 activation and IL-4 production.…”

Section: Discussionsupporting

confidence: 83%

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Intracellular Thiols Contribute to Th2 Function via a Positive Role in IL-4 Production

Monick

Samavati

Butler

et al. 2003

The Journal of Immunology

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A number of lung diseases, including many interstitial lung diseases and HIV infection, are associated with decreases in intracellular thiols. Altered Th1/Th2 T cell balance has also been associated with disease progression in many of the same diseases. IFN-γ and IL-4 are critical effector cytokines of Th1 and Th2 cells, respectively. To determine the effect of thiols on the production of IFN-γ and IL-4 by splenocytes, cells were incubated in the presence and the absence of N-acetylcysteine (NAC) and stimulated with αCD3 or αCD3 and IL-12. Augmenting intracellular soluble thiol pools (∼2-fold) with 15 mM NAC blocked induction of IFN-γ and increased production of IL-4 without causing significant changes in intracellular glutathione levels. The effect of NAC on IL-4 production was not linked to an increase in STAT6 phosphorylation, as STAT6 levels were decreased, nor did the increase in IL-4 occur with purified CD4 cells. We found that NAC increased splenocyte IL-4 production via an effect on APCs. We also found that NAC increased two IL-4 relevant transcription factors (AP-1) and NFATc. These studies suggest that increasing intracellular reduced thiol pools decreases IL-12 signaling and IFN-γ production, while increasing IL-4 production. The sum of these effects may contribute to alterations in the balance between Th1 and Th2 responses in lung diseases associated alterations in intracellular thiol pools.

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Section: Discussionsupporting

confidence: 83%

“…STAT6 knockout mice exhibit a defect in Th2 response development, defective IgE class switching, and defects in Ag-induced airway eosinophilia (19,20). Importantly, there are also studies which suggest that STAT6-independent Th2 differentiation can occur and that STAT6 can be activated independently of IL-4 and IL-13 receptor signaling (21,22).…”

mentioning

confidence: 99%

Intracellular Thiols Contribute to Th2 Function via a Positive Role in IL-4 Production

Monick

Samavati

Butler

et al. 2003

The Journal of Immunology

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“…N. brasiliensis inoculation and GaMD immunization each stimulate a strong Th2 response (58). In both cases, sIL-4R␣ concentrations increased 2-3-fold and sIL-13R␣2 concentrations increased 7-10-fold as the Th2 response peaked and then decreased back toward baseline levels (Fig.…”

Section: Worm Infection and Ag Immunization Induce A Greater Increasementioning

confidence: 87%

Differences in Expression, Affinity, and Function of Soluble (s)IL-4Rα and sIL-13Rα2 Suggest Opposite Effects on Allergic Responses

Khodoun

Lewis²,

Yang

et al. 2007

The Journal of Immunology

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IL-4 and IL-13 are each bound by soluble receptors (sRs) that block their activity. Both of these sRs (sIL-4Rα and sIL-13Rα2) are present in low nanogram per milliliter concentrations in the serum from unstimulated mice, but differences in affinity and half-life suggest differences in function. Serum IL-4/sIL-4Rα complexes rapidly dissociate, releasing active IL-4, whereas sIL-13Rα2 and IL-13 form a stable complex that has a considerably longer half-life than uncomplexed IL-13, sIL-13Rα2, IL-4, or sIL-4Rα. Approximately 25% of sIL-13Rα2 in serum is complexed to IL-13; this percentage and the absolute quantity of sIL-13Rα2 in serum increase considerably during a Th2 response. sIL-13Rα2 gene expression is up-regulated by both IL-4 and IL-13; the effect of IL-4 is totally IL-4Rα-dependent while the effect of IL-13 is partially IL-4Rα-independent. Inhalation of an IL-13/sIL-13Rα2 complex does not affect the expression of IL-13-inducible genes but increases the expression of two genes, Vnn1 and Pira-1, whose products activate APCs and promote neutrophilic inflammation. These observations suggest that sIL-4Rα predominantly sustains, increases, and diffuses the effects of IL-4, whereas sIL-13Rα2 limits the direct effects of IL-13 to the site of IL-13 production and forms a stable complex with IL-13 that may modify the quality and intensity of an allergic inflammatory response.

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“…Significant numbers of IFNg-producing cells were found in Gata3 fl/fl OX40-Cre mice after infection [43]. Thus, although the Th2 response to helminth infection is IL-4/Stat6 independent [51][52][53][54], it is GATA-3 dependent.…”

Section: The Central Role Of Gata-3 In Reinforcing Th2 Responsesmentioning

confidence: 93%

GATA-3 promotes Th2 responses through three different mechanisms: induction of Th2 cytokine production, selective growth of Th2 cells and inhibition of Th1 cell-specific factors

et al. 2006

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Naïve CD4 T cells can differentiate into at least two different types of T helpers, Th1 and Th2 cells. Th2 cells, capable of producing IL-4, IL-5 and IL-13, are involved in humoral immunity against extracellular pathogens and in the induction of asthma and other allergic diseases. In this review, we summarize recent reports regarding the transcription factors involved in Th2 differentiation and cell expansion, including Stat5, Gfi-1 and GATA-3. Stat5 activation is necessary and sufficient for IL-2-mediated function in Th2 differentiation. Enhanced Stat5 signaling induces Th2 differentiation independent of IL-4 signaling; although it does not up-regulate GATA-3 expression, it does require the presence of GATA-3 for its action. Gfi-1, induced by IL-4, promotes the expansion of GATA-3-expressing cells. Analysis of conditional Gata3 knockout mice confirmed the critical role of GATA-3 in Th2 cell differentiation (both IL-4 dependent and IL-4 independent) and in Th2 cell proliferation and also showed the importance of basal GATA-3 expression in inhibiting Th1 differentiation.

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Stat6 Regulation of In Vivo IL-4 Responses

Cited by 171 publications

References 78 publications

Intracellular Thiols Contribute to Th2 Function via a Positive Role in IL-4 Production

Intracellular Thiols Contribute to Th2 Function via a Positive Role in IL-4 Production

Differences in Expression, Affinity, and Function of Soluble (s)IL-4Rα and sIL-13Rα2 Suggest Opposite Effects on Allergic Responses

GATA-3 promotes Th2 responses through three different mechanisms: induction of Th2 cytokine production, selective growth of Th2 cells and inhibition of Th1 cell-specific factors

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