IL-4 stimulates mouse macrophages to express APRIL through p38MAPK and two different downstream molecules, CREB and Stat6

Jang, Young‐Saeng; Kim, Hyun-A; Park, Seok‐Rae; Lee, Mi-Ra; Park, Jae-Bong; Kim, Pyeung-Hyeun

doi:10.1016/j.cyto.2009.04.005

Cited by 13 publications

(11 citation statements)

References 29 publications

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“…Thus, some authors have reported that IL‐4 is unable to activate p38 MAPK in murine macrophages and human monocytes . In contrast, others studies have demonstrated that IL‐4 enhances the levels of p38 MAPK in the THP‐1 human cell line and in the P388D1 mouse macrophage cell line . Our study showed that IL‐4 induced p38 MAPK activation in thyoglicollate elicited peritoneal mouse macrophages and in the mouse macrophage cell line J744.…”

Section: Discussioncontrasting

confidence: 56%

Critical role of p38 MAPK in IL‐4‐induced alternative activation of peritoneal macrophages

et al. 2014

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Alternative activation of macrophages plays an important role in a range of physiological and pathological processes. This alternative phenotype, also known as M2 macrophages, is induced by type 2 cytokines such as IL-4. The binding of IL-4 to its receptor leads to activation of two major signaling pathways: STAT-6 and PI3K. However, recent studies have described that p38 MAPK might play a role in IL-4-dependent signaling in some cells, although its role in macrophages is still controversial. In this study, we investigated whether p38 MAPK plays a role in the polarization of macrophages in mice. Our results reveal that IL-4 induces phosphorylation of p38 MAPK in thioglycollate-elicited murine peritoneal macrophages, in addition to STAT-6 and PI3K activation. Furthermore, p38 MAPK inactivation, by gene silencing or pharmacological inhibition, suppressed IL-4-induced typical M2 markers, indicating the involvement of p38 MAPK in the signaling of IL-4 leading to M2-macrophage polarization. Moreover, p38 MAPK inhibition blocked phosphorylation of STAT-6 and Akt, suggesting that p38 MAPK is upstream of these signaling pathways. Finally, we show that in an in vivo model of chitin-induced M2 polarization, p38 MAPK inhibition also diminished activation of M2 markers. Taken together, our data establish a new role for p38 MAPK during IL-4-induced alternative activation of macrophages.Keywords: Alternative activation r Chitin r IL-4 r JAK/STAT r Macrophages r p38 MAPK Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMacrophages represent an essential cell population of innate immunity that plays a critical role in inflammation and host defense as well as in the maintenance of tissue homeostasis [1]. Two major macrophage phenotypes have been characterized according to the activation by different microenvironmental signals: the classically activated macrophages (M1) and the alternatively activated macrophages (M2) [1,2]. M1 macrophages Correspondence: Dr. Sonsoles Hortelano e-mail: shortelano@isciii.es develop in response to proinflammatory stimuli like IFN-γ or IL-1β and bacterial products such as LPS. This phenotype has antimicrobial and cytotoxic functions and is characterized by enhanced production of proinflammatory cytokines, expression of MHC class II molecules, and generation of free radicals including nitric oxide (NO). In contrast, M2 macrophages differentiate in the presence of cytokines as IL-4 or IL-13. They have enhanced capacity for endocytosis but reduced motility and cytotoxic effects, showing both anti-inflammatory activities and a tissue-repair function. In addition, these M2 macrophages express a different subset of innate immunity molecules as compared to M1 macrophages [3,4]. Expression of arginase-1 (Arg-1), the mannose receptor (MR), and genes involved in tissue remodeling such as chitinase 3-like 3 C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 274Lidia Jiménez-Garcia et al. Eur. J. Immunol. 2015. 45: 27...

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Section: Discussioncontrasting

confidence: 56%

Critical role of p38 MAPK in IL‐4‐induced alternative activation of peritoneal macrophages

et al. 2014

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“…Also relevant is the recent study by Thornton et al (26), which showed that GSK-3b can be phosphorylated (and inactivated) via phosphorylation at serine 389 by p38 MAPK. This appears to be the main pathway of IL-13 inactivation of GSK-3b, because we present evidence that IL-13 phosphorylation of GSK-3b does not depend on PI3K/Akt; instead, it depends, at least partially, on p38 MAPK, a kinase known to be induced via STAT6 signaling (38). On this basis, a reasonable interpretation of the data is that, although IL-13-induced phosphorylation and inactivation of GSK-3b via p38 MAPK are persistent, TLR activation of GSK-3b via this kinase is transient; thus, IL-13 inactivation of GSK-3b is not redundant with TLR inactivation of GSK-3b in the context of colitis resolution.…”

Section: Discussionmentioning

confidence: 94%

IL-13 Orchestrates Resolution of Chronic Intestinal Inflammation via Phosphorylation of Glycogen Synthase Kinase-3β

Fichtner‐Feigl

Kesselring

Martı́n

et al. 2014

The Journal of Immunology

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Spontaneous amelioration of inflammation (often accompanied by fibrosis) is a well-known, but poorly understood, outcome of many chronic inflammatory processes. We studied this phenomenon in a chronic trinitrobenzene sulfonic acid–induced colitis model, an experimental colitis in mice that we showed to ultimately undergo spontaneous resolution, despite continued trinitrobenzene sulfonic acid stimulation. Analysis of the mechanism of this resolution revealed that it was critically dependent on IL-13 activation of STAT6, followed by phosphorylation (inactivation) of glycogen synthase kinase-3β, at least in part via STAT6 induction of p38 MAPK. Such glycogen synthase kinase-3β inactivation causes changes in CREB and p65 DNA-binding activity that favors decreased proinflammatory IL-17 production and increased anti-inflammatory IL-10 production. Thus, in this case, IL-13 acts as a molecular switch that leads to resolution of inflammation.

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“…IL-4 is also known to initiate activation of MEK subfamilies, including ERK1/2, in bronchial smooth muscle and epithelial cells (Kelly-Welch et al , 2003). Finally, more recent data identify P38MAPK as an additional mediator of IL-4R signaling (Canfield et al , 2005; Jang et al , 2009). …”

Section: Resultsmentioning

confidence: 99%

Human epicardium-derived cells fuse with high efficiency with skeletal myotubes and differentiate toward the skeletal muscle phenotype: a comparison study with stromal and endothelial cells

Gentile

Toietta

Pazzano

et al. 2011

MBoC

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IL-4 stimulates mouse macrophages to express APRIL through p38MAPK and two different downstream molecules, CREB and Stat6

Cited by 13 publications

References 29 publications

Critical role of p38 MAPK in IL‐4‐induced alternative activation of peritoneal macrophages

Critical role of p38 MAPK in IL‐4‐induced alternative activation of peritoneal macrophages

IL-13 Orchestrates Resolution of Chronic Intestinal Inflammation via Phosphorylation of Glycogen Synthase Kinase-3β

Human epicardium-derived cells fuse with high efficiency with skeletal myotubes and differentiate toward the skeletal muscle phenotype: a comparison study with stromal and endothelial cells

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