The biology of Stat4 and Stat6

Wurster, Andrea L.; Tanaka, Takashi; Grusby, Michael J.

doi:10.1038/sj.onc.1203485

Cited by 288 publications

(237 citation statements)

References 107 publications

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“…We selected the IL-7 receptor endodomain component of our ICR since this cytokine is a prototypic Th1 cytokine, 48,49 and both IL-4 and IL-7 are common gamma chain cytokines. 50 Hence, upon IL-4 engagement our 4/7 ICR can dimerize with the ubiquitous IL-2 common gamma chain and transmit a signal via the IL-7 receptor endodomain (Figure 2), [50][51][52][53] supporting cell proliferation and the development of T cell memory, thereby enhancing the overall anti-tumor response.…”

Section: Discussionmentioning

confidence: 99%

Improving Chimeric Antigen Receptor-Modified T Cell Function by Reversing the Immunosuppressive Tumor Microenvironment of Pancreatic Cancer

Sukumaran²,

et al. 2017

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Section: Discussionmentioning

confidence: 99%

Improving Chimeric Antigen Receptor-Modified T Cell Function by Reversing the Immunosuppressive Tumor Microenvironment of Pancreatic Cancer

Sukumaran²,

et al. 2017

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“…The binding of IL-4 to IL-4R triggers the phosphorylation of JAK-1 and JAK-3, 65 leading to activation of the major IL-4 signaling pathway mediated by STAT-6. 66 Tyrosine-phosphorylated STAT-6 forms homodimers and translocates to the nucleus, where it binds IL-4-responsive elements and induces gene transcription. 67 It has been shown elsewhere that in mouse nonhepatic fibroblasts, IL-4 can induce collagen I production through a mechanism involving STAT-6 and the activation of transcription factors, 68 and that the promoter region of collagen type I DNA contains a STAT-6-responsive element.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-4 induces the activation and collagen production of cultured human intrahepatic fibroblasts via the STAT-6 pathway

Aoudjehane

Pissaia

Scatton

et al. 2008

Laboratory Investigation

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Interleukin-4 (IL-4) is overexpressed in liver grafts in a context of severe recurrent hepatitis C, during which the development of fibrosis is dramatically accelerated. In this study, we examined the effects of IL-4 on the activation and collagen production of cultured human intrahepatic (myo)fibroblasts (hIHFs), and investigated the underlying mechanisms. The myofibroblastic nature of cells was evaluated morphologically using activation markers (smooth muscle a-actin, vimentin and prolyl 4-hydroxylase). Quiescent hIHFs were obtained by cell incubation in serum-free medium or cell culture on Matrigel. We first analyzed IL-4 receptor expression, STAT-6 activation by IL-4, and STAT-6 inhibition by an anti-IL-4 antibody or by STAT-6 small-interfering RNA (siRNA) transfection. We then focused on collagen production, using quantitative real-time PCR to analyze the effect of IL-4 on the mRNA expression of collagens I, III and IV, and on collagen levels in supernatants of hIHFs, using the Sircol collagen assay. hIHFs cultured in plastic wells appeared to be morphologically activated. The expression of activation markers was reduced by serum deprivation or culture on Matrigel, and restored by IL-4 incubation. The IL-4 receptor was expressed by hIHFs, and STAT-6 was activated following incubation with IL-4. Both anti-IL-4 antibody and STAT-6 siRNA transfection inhibited this activation. The treatment of hIHFs with IL-4 increased the mRNA expression of collagens I, III and IV (Po0.05) and elevated collagen levels in supernatants (P ¼ 0.01 vs untreated cells). Therefore, IL-4 exerts profibrotic effects by activating hIHFs and inducing collagen production and secretion. This effect requires IL4-R binding and STAT-6 activation. IL-4 may thus be involved in accelerated course of fibrogenesis during recurrent hepatitis C.

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“…Th2 cytokines IL-4 and IL-13, which are locally produced in tissues, exert their biologically effects via activation of the transcription factor STAT6 (14). Confirming the importance of this pathway in antihelminth immunity and allergies, mice lacking STAT6 are severely compromised in their ability to mount allergic inflammatory responses (15,16) or defend against various gastronintestinal helminths (12,17).…”

mentioning

confidence: 99%

IL-4/STAT6 immune axis regulates peripheral nutrient metabolism and insulin sensitivity

Ricardo-González

Eagle²,

Odegaard³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

223

190

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Immune cells take residence in metabolic tissues, providing a framework for direct regulation of nutrient metabolism. Despite conservation of this anatomic relationship through evolution, the signals and mechanisms by which the immune system regulates nutrient homeostasis and insulin action remain poorly understood. Here, we demonstrate that the IL-4/STAT6 immune axis, a key pathway in helminth immunity and allergies, controls peripheral nutrient metabolism and insulin sensitivity. Disruption of signal transducer and activator of transcription 6 (STAT6) decreases insulin action and enhances a peroxisome proliferator-activated receptor α (PPARα) driven program of oxidative metabolism. Conversely, activation of STAT6 by IL-4 improves insulin action by inhibiting the PPARα-regulated program of nutrient catabolism and attenuating adipose tissue inflammation. These findings have thus identified an unexpected molecular link between the immune system and macronutrient metabolism, suggesting perhaps the coevolution of these pathways occurred to ensure access to glucose during times of helminth infection.insulin resistance | obesity | cytokines | liver | Th2 immunity

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The biology of Stat4 and Stat6

Cited by 288 publications

References 107 publications

Improving Chimeric Antigen Receptor-Modified T Cell Function by Reversing the Immunosuppressive Tumor Microenvironment of Pancreatic Cancer

Improving Chimeric Antigen Receptor-Modified T Cell Function by Reversing the Immunosuppressive Tumor Microenvironment of Pancreatic Cancer

Interleukin-4 induces the activation and collagen production of cultured human intrahepatic fibroblasts via the STAT-6 pathway

IL-4/STAT6 immune axis regulates peripheral nutrient metabolism and insulin sensitivity

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