The kinases MSK1 and MSK2 act as negative regulators of Toll-like receptor signaling

Ananieva, Olga; Darragh, Joanne; Johansen, Claus; Carr, Julia M.; McIlrath, Joanne; Park, Jin Mo; Wingate, Andrew D.; Monk, Claire E.; Toth, Rachel; Santos, Susana G.; Iversen, Lars; Arthur, J. Simon C.

doi:10.1038/ni.1644

Cited by 292 publications

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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: 63%

“…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: 56%

“…However, CREB has recently been found to be phosphorylated downstream of p38 [65], and CREB can also be phosphorylated downstream of ERK1/2. In both cases, CREB is not phosphorylated directly by MAPK, but by MSK1/2, kinases activated by either the ERK1/2 or p38 MAPK [25,26,66]. It is worth noting that for some stimuli, including LPS, the inhibition of ERK1/2 and also p38 is required to block MSK activation and CREB phosphorylation [25].…”

Section: Discussionmentioning

confidence: 98%

“…In both cases, CREB is not phosphorylated directly by MAPK, but by MSK1/2, kinases activated by either the ERK1/2 or p38 MAPK [25,26,66]. It is worth noting that for some stimuli, including LPS, the inhibition of ERK1/2 and also p38 is required to block MSK activation and CREB phosphorylation [25]. Therefore, for genes regulated by CREB, studies that examine only the inhibition of a single MAPK pathway may miss some of the effects of that pathway.…”

mentioning

confidence: 95%

“…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: 63%

mentioning

confidence: 56%

Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 95%

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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The long noncoding RNA MALAT1 regulates the lipopolysaccharide‐induced inflammatory response through its interaction with NF‐κB

et al. 2016

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MALAT1 is a conserved long noncoding RNA whose expression correlates with many human cancers. However, its significance in immunity remains largely unknown. Here, we observe that MALAT1 is upregulated in lipopolysaccharide (LPS)-activated macrophages. Knockdown of MALAT1 increases LPS-induced expression of TNFa and IL-6. Mechanistically, MALAT1 was found to interact with NF-jB in the nucleus, thus inhibiting its DNA binding activity and consequently decreasing the production of inflammatory cytokines. Additionally, abnormal expression of MALAT1 was found to be NFjB-dependent. These findings suggest that MALAT1 may function as an autonegative feedback regulator of NF-jB to help fine-tune innate immune responses.

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Genetics of Primary Biliary Cirrhosis

Mells

Hirschfield

2013

Encyclopedia of Life Sciences

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Primary biliary cirrhosis (PBC) is an autoimmune liver disease affecting 0.1% of women over the age of 40 years. PBC is characterised by autoreactive T‐cells and B‐cells specific for mitochondrial self‐antigens, typically the E2‐domain of pyruvate dehydrogenase complex (PDC‐E2), which mediate progressive destruction of the small, intrahepatic bile ducts, eventually leading to cirrhosis. It is believed that environmental factors trigger loss of immune tolerance to PDC‐E2 in those individuals with a genetic predisposition towards PBC. Knowledge of the genetic basis of PBC has improved following four genome‐wide association studies and two immunochip association studies of PBC, undertaken in large case‐control cohorts from North America, Europe and Japan. These studies have clarified the well‐established human leucocyte antigen (HLA) association and identified 27 non‐HLA risk loci, which harbour highly plausible candidate genes, mainly involved in regulation of the immune system. Key Concepts: Primary biliary cirrhosis (PBC) is a chronic, cholestatic liver disease characterised by progressive, autoimmune destruction of the small, interlobular bile ducts, leading in many cases to end‐stage liver disease with attendant need for liver transplantation. PBC is a complex disorder, meaning that it results from an interaction of genetic and environmental factors. Genome‐wide association studies (GWAS) and iCHIP studies of PBC have substantially improved knowledge of the genetic architecture of PBC. To date, four GWAS and two iCHIP studies of PBC have been undertaken in populations of European or Japanese ancestry. The HLA complex makes an important contribution to the genetic basis of PBC. Risk haplotypes associated with PBC include those carrying DRB1*08 and DRB1*04 alleles. Protective haplotypes include those carrying DRB1*11 and DRB1*15 alleles. A total of 27 non‐HLA risk loci for PBC have been identified in GWAS or iCHIP studies. Many loci harbour highly plausible candidate genes, mainly involved in innate or acquired immune processes. Many risk loci for PBC are also the risk loci for other autoimmune conditions, such as multiple sclerosis, coeliac disease or inflammatory bowel disease. The genetic architecture of PBC in the Japanese population appears to be distinct from the genetic architecture of PBC in populations of European ancestry. This suggests that susceptibility to PBC is characterised by genetic heterogeneity. Known independent risk variants for PBC account for less than 20% of PBC heritability. This is an example of ‘missing heritability’. The iCHIP studies of PBC suggest that PBC risk loci may be polymorphic. The iCHIP studies of PBC suggest that rare and low‐frequency variants make a substantial contribution to the genetic variance of the diseases; identification of rare variants will require large‐scale sequencing efforts.

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The kinases MSK1 and MSK2 act as negative regulators of Toll-like receptor signaling

Cited by 292 publications

References 51 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

The long noncoding RNA MALAT1 regulates the lipopolysaccharide‐induced inflammatory response through its interaction with NF‐κB

Genetics of Primary Biliary Cirrhosis

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