The kinase p38α serves cell type–specific inflammatory functions in skin injury and coordinates pro- and anti-inflammatory gene expression

Kim, Chun; Sano, Yasuyo; Todorovа, Katerina; Carlson, Bradley A.; Arpa, Luis; Celada, Antonio; Lawrence, Toby; Otsu, Kinya; Brissette, Janice L.; Arthur, J. Simon C.; Park, Jin Mo

doi:10.1038/ni.1640

Cited by 244 publications

(285 citation statements)

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“…CREB is implicated in MKP-1 expression, as shown in this study and others [25,26,62]. CREB may be phosphorylated by kinases [53] that are induced by M-CSF, such as PI-3K [63], or PKA induced by LPS [64].…”

Section: Discussionsupporting

confidence: 65%

“…For example, ERK5 induced phosphorylation of the transcription factor monocyte-specific enhancer binding factor 2c, whose activation increases c-Jun expression [60]. In relation to the phosphorylation of c-jun by JNK-1, this effect could be exerted through translocation to the nucleus [61], where JNK-1 phosphorylates c-Jun and thereby enhances its transcriptional activity [54].CREB is implicated in MKP-1 expression, as shown in this study and others [25,26,62]. CREB may be phosphorylated by kinases [53] that are induced by M-CSF, such as PI-3K [63], or PKA induced by LPS [64].…”

mentioning

confidence: 60%

“…In the macrophagic cell line RAW264.7, MKP-1 induction by LPS is regulated mainly by ERK and modulated by p38 [24]. In bone marrow-derived macrophages, LPS-induced MKP-1 expression is partially blocked when the inhibitors of ERK and p38 were used together [25] or when cells from the p38 KO were used [26]. Results from our group show that the activation of the MEK/ERK-1/2 cascade is not required for the induction of MKP-1 expression in macrophages [15,16].…”

Section: Introductionmentioning

confidence: 99%

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CREB and AP‐1 activation regulates MKP‐1 induction by LPS or M‐CSF and their kinetics correlate with macrophage activation versus proliferation

et al. 2009

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MAPK phosphatase-1 (MKP-1) is a protein phosphatase that plays a crucial role in innate immunity. This phosphatase inactivates ERK1/2, which are involved in two opposite functional activities of the macrophage, namely proliferation and activation. Here we found that although macrophage proliferation and activation induce MKP-1 with different kinetics, gene expression is mediated by the proximal promoter sequences localized between À380 and À180 bp. Mutagenesis experiments of the proximal element determined that CRE/AP-1 is required for LPS-or M-CSF-induced activation of the MKP-1 gene. Moreover, the results from gel shift analysis and chromatin immunoprecipitation indicated that c-Jun and CREB bind to the CRE/AP-1 box. The distinct kinetics shown by M-CSF and LPS correlates with the induction of JNK and c-jun, as well as the requirement for Raf-1. The signal transduction pathways that activate the induction of MKP-1 correlate kinetically with induction by M-CSF and LPS.Key words: Activation . Kinases . Macrophage . Phosphatases . Proliferation IntroductionMacrophages perform critical functions during the immune response. These cells are regulators of homeostasis and play an important role in innate and acquired immunity during infection, tumor growth, and wound healing [1]. In response to needs, tissue macrophages proliferate, further differentiate to more specialized macrophagic populations, or become activated. Macrophages, like many other cells of the immune system, are produced in large excess and most undergo apoptosis [2].In the presence of M-CSF, macrophages differentiate and proliferate. However, the proliferation of these cells is blocked when they are activated by Gram-negative LPS or by . Activation causes many biochemical, morphological and functional modifications. Macrophage response to M-CSF and LPS involves the phosphorylation of the three members of the MAPK family [4].MAPK are critical components of signal transduction pathways activated by a range of stimuli and they mediate a number of physiological and pathological changes in cell function [5,6]. MAPK activation requires phosphorylation on a threonine and tyrosine residue located in the activation loop. This process is reversible even in the continued presence of activating stimuli, thereby indicating that protein phosphatases regulate MAPK [7]. Although MAPK are conserved evolutionary pathways present in eukaryotic cells, the kinetics of activation and their subcellular compartmentalization are cell type-specific, and they orchestrate differential cellular responses. For example, in neuronal cells, sustained MAPK phosphorylation of even days is required for cellular activation or differentiation, while in fibroblasts, phosphorylation of this kinase family is very short. In contrast, to Immunol. 2009. 39: 1902-1913 Cristina Casals-Casas et al. 1902 achieve proliferation, extended activation of MAPK is required in these cells [6,7]. The correct spatio-temporal regulation of MAPK signalling is crucial in determining cellular responses to g...

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Section: Discussionsupporting

confidence: 65%

mentioning

confidence: 60%

Section: Introductionmentioning

confidence: 99%

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CREB and AP‐1 activation regulates MKP‐1 induction by LPS or M‐CSF and their kinetics correlate with macrophage activation versus proliferation

et al. 2009

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“…MAPKs include ERK, JNK and p38 MAPK, and control a wide spectrum of cellular processes (Kim et al 2008a). Accumulating evidence indicated that MAPKs actively participated in the regulation of autophagic process (Peter et al 2010).…”

Section: Discussionmentioning

confidence: 99%

“…In Parkinson’s and Lewy body diseases, human tissue study supports a role for ERK/MAPK in the regulation of autophagy (Jung et al 2010). In colorectal cancer cells, a novel cell type-specific role of p38α MAPK is found to control and mediate autophagy (Kim et al 2008a). Either autophagy or apoptosis has been found to be regulated by JNK-mediated Bcl-2 phosphorylation (Kim et al 2008b).…”

Section: Discussionmentioning

confidence: 99%

Rasfonin promotes autophagy and apoptosis via upregulation of reactive oxygen species (ROS)/JNK pathway

Sun

Che²,

Jiang

2016

Mycology

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Rasfonin is a fungal secondary metabolite demonstrating with antitumour effects. Reactive oxygen species (ROS) are formed as a natural by-product of the normal metabolism of oxygen and have important roles in cell signalling and homeostasis. Studies reported that many fungal secondary metabolites activated either autophagy or apoptosis through ROS generation. In former study, we revealed that rasfonin induced both autophagy and apoptosis, however, whether it promoted aforementioned processes via upregulation of ROS generation remains explored. In the current work, we demonstrated that rasfonin induced autophagy and apoptosis concomitant with a dramatically ROS production. N-Acetylcysteine (NAC), an often used ROS inhibitor, decreased both autophagic flux and caspase-dependent apoptosis by rasfonin. Flow cytometry analysis revealed NAC was able to reduce rasfonin-dependent apoptosis and necrosis. In methanethiosulfonate (MTS) assay, we observed that NAC significantly blocked rasfonin-induced cell viability loss. In addition, we found that rasfonin increased the phosphorylation of c-Jun NH2-terminal kinase (JNK), which was inhibited by NAC. SP600125, an inhibitor of JNK, reduced rasfonin-dependent autophagic flux and apoptosis. Moreover, we demonstrated that rasfonin inhibited the phosphorylation of both 4E-binding protein 1 (4E-BP1) and S6 kinase 1 (S6K1), two main substrates of mammalian target of rapamycin (mTOR). Collectively, rasfonin activated autophagy and apoptosis through upregulation of ROS/JNK signalling.

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Modulation of Cerebrospinal Fluid Dysregulation via a SPAK and OSR1 Targeted Framework Nucleic Acid in Hydrocephalus

Wang,

Cheng,

Liu

et al. 2024

Advanced Science

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Hydrocephalus is one of the most common brain disorders and a life‐long incurable condition. An empirical “one‐size‐fits‐all” approach of cerebrospinal fluid (CSF) shunting remains the mainstay of hydrocephalus treatment and effective pharmacotherapy options are currently lacking. Macrophage‐mediated ChP inflammation and CSF hypersecretion have recently been identified as a significant discovery in the pathogenesis of hydrocephalus. In this study, a pioneering DNA nano‐drug (TSOs) is developed by modifying S2 ssDNA and S4 ssDNA with SPAK ASO and OSR1 ASO in tetrahedral framework nucleic acids (tFNAs) and synthesis via a one‐pot annealing procedure. This construct can significantly knockdown the expression of SPAK and OSR1, along with their downstream ion channel proteins in ChP epithelial cells, thereby leading to a decrease in CSF secretion. Moreover, these findings indicate that TSOs effectively inhibit the M0 to M1 phenotypic switch of ChP macrophages via the MAPK pathways, thus mitigating the cytokine storm. In in vivo post‐hemorrhagic hydrocephalus (PHH) models, TSOs significantly reduce CSF secretion rates, alleviate ChP inflammation, and prevent the onset of hydrocephalus. These compelling results highlight the potential of TSOs as a promising therapeutic option for managing hydrocephalus, with significant applications in the future.

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The kinase p38α serves cell type–specific inflammatory functions in skin injury and coordinates pro- and anti-inflammatory gene expression

Cited by 244 publications

References 50 publications

CREB and AP‐1 activation regulates MKP‐1 induction by LPS or M‐CSF and their kinetics correlate with macrophage activation versus proliferation

CREB and AP‐1 activation regulates MKP‐1 induction by LPS or M‐CSF and their kinetics correlate with macrophage activation versus proliferation

Rasfonin promotes autophagy and apoptosis via upregulation of reactive oxygen species (ROS)/JNK pathway

Modulation of Cerebrospinal Fluid Dysregulation via a SPAK and OSR1 Targeted Framework Nucleic Acid in Hydrocephalus

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