Signaling Pathways and Genes that Inhibit Pathogen-Induced Macrophage Apoptosis— CREB and NF-κB as Key Regulators

Park, Jin Mo; Greten, Florian R.; Wong, Athena W.; Westrick, Randal J.; Arthur, J. Simon C.; Otsu, Kinya; Hoffmann, Alexander; Montminy, Marc; Karin, Michael

doi:10.1016/j.immuni.2005.08.010

Cited by 298 publications

(277 citation statements)

References 57 publications

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“…PAI-2 expression in monocytes and macrophages is up-regulated rapidly, mainly through IKK/NF-κB activation, after stimulation with inflammatory mediators and pathogens (13). PAI-2 suppresses apoptosis and IL-1β-driven inflammation, although the underlying mechanisms are poorly understood (13,15).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, PAI-2 has been associated with newly identified uPA-independent biological functions, probably through targeting an as yet uncharacterized intracellular molecule (11). In addition, PAI-2 is one of the major molecules up-regulated in macrophages in response to TLR4 activators or inflammatory mediators, suggesting its function in the regulation of innate immunity (12,13).…”

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confidence: 99%

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TLR-induced PAI-2 expression suppresses IL-1β processing via increasing autophagy and NLRP3 degradation

Chuang

Yang

Chou

et al. 2013

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

136

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The NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome, a multiprotein complex, triggers caspase-1 activation and maturation of the proinflammatory cytokines IL-1β and IL-18 upon sensing a wide range of pathogen-and damage-associated molecules. Dysregulation of NLRP3 inflammasome activity contributes to the pathogenesis of many diseases, but its regulation remains poorly defined. Here we show that depletion of plasminogen activator inhibitor type 2 (PAI-2), a serine protease inhibitor, resulted in NLRP3-and ASC (apoptosis-associated Specklike protein containing a C-terminal caspase recruitment domain)-dependent caspase-1 activation and IL-1β secretion in macrophages upon Toll-like receptor 2 (TLR2) and TLR4 engagement. TLR2 or TLR4 agonist induced PAI-2 expression, which subsequently stabilized the autophagic protein Beclin 1 to promote autophagy, resulting in decreases in mitochondrial reactive oxygen species, NLRP3 protein level, and pro-IL-1β processing. Likewise, overexpressing Beclin 1 in PAI-2-deficient cells rescued the suppression of NLRP3 activation in response to LPS. Together, our data identify a tier of TLR signaling in controlling NLRP3 inflammasome activation and reveal a cell-autonomous mechanism which inversely regulates TLR-or Escherichia coli-induced mitochondrial dysfunction, oxidative stress, and IL-1β-driven inflammation.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

TLR-induced PAI-2 expression suppresses IL-1β processing via increasing autophagy and NLRP3 degradation

Chuang

Yang

Chou

et al. 2013

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

136

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“…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: 99%

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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“…More recently, it has been shown that transcription of the serpin plasminogen activator inhibitor 2 (PAI-2) is induced by the cooperation of both CREB and NF-kB. 7 A new function of IKK1 has been identified in macrophages. Two different groups showed that whereas IKK2 is involved in NF-kB activation in macrophages, IKK1 actually inhibits NFkB activation in these cells.…”

Section: Nf-jb and Macrophage Activitymentioning

confidence: 99%

NF-κB and the regulation of hematopoiesis

2006

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Signaling Pathways and Genes that Inhibit Pathogen-Induced Macrophage Apoptosis— CREB and NF-κB as Key Regulators

Cited by 298 publications

References 57 publications

TLR-induced PAI-2 expression suppresses IL-1β processing via increasing autophagy and NLRP3 degradation

TLR-induced PAI-2 expression suppresses IL-1β processing via increasing autophagy and NLRP3 degradation

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

NF-κB and the regulation of hematopoiesis

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