Deacetylase Activity Is Required for STAT5-Dependent GM-CSF Functional Activity in Macrophages and Differentiation to Dendritic Cells

Sebastián, Carlos; Serra, Maria Paola; Yeramian, Andrée; Serrat, Neus; Lloberas, Jorge; Celada, Antonio

doi:10.4049/jimmunol.180.9.5898

Cited by 49 publications

(44 citation statements)

References 63 publications

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“…Cells (20 Â 10 6 ) were cross-linked with 1% paraformaldehyde for 20 min at room temperature [74]. After two washes with ice-cold PBS, cells were collected in 3 mLl of 0.1 M Tris-HCl pH 9.4, 10 mM DTT with a scraper and were incubated for 15 min at 301C.…”

Section: Chip Assaymentioning

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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Section: Chip Assaymentioning

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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“…A recent study showed that trichostatin A, a pan-HDAC inhibitor, blocked the effects of GM-CSF on macrophage proliferation as well as on generation of DCs (45). Our studies focused on the bacterial fermentation products acetate, propionate, and butyrate.…”

Section: Figure 5 Role Of Hdacs In DC Development a Linmentioning

confidence: 99%

Blockade of Dendritic Cell Development by Bacterial Fermentation Products Butyrate and Propionate through a Transporter (Slc5a8)-dependent Inhibition of Histone Deacetylases

Singh

Thangaraju

Prasad

et al. 2010

Journal of Biological Chemistry

234

165

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Mammalian colon harbors trillions of bacteria, yet there is no undue inflammatory response by the host against these bacteria under normal conditions. The bacterial fermentation products acetate, propionate, and butyrate are believed, at least in part, to be responsible for these immunosuppressive effects. Dendritic cells play an essential role in presentation of antigens to T lymphocytes and initiation of adaptive immune responses. Here we report that butyrate and propionate block the generation of dendritic cells from bone marrow stem cells, without affecting the generation of granulocytes. This effect is dependent on the Na ؉ -coupled monocarboxylate transporter Slc5a8, which transports butyrate and propionate into cells, and on the ability of these two bacterial metabolites to inhibit histone deacetylases. Acetate, which is also a substrate for Slc5a8 but not an inhibitor of histone deacetylases, does not affect dendritic cell development, indicating the essential role of histone deacetylase inhibition in the process. The blockade of dendritic cell development by butyrate and propionate is associated with decreased expression of the transcription factors PU.1 and RelB. Butyrate also elicits its biologic effects through its ability to activate the G-proteincoupled receptor Gpr109a, but this mechanism is not involved in butyrate-induced blockade of dendritic cell development. The participation of Slc5a8 and the non-involvement of Gpr109a in butyrate effects have been substantiated using bone marrow cells obtained from Slc5a8 ؊/؊ and Gpr109a ؊/؊ mice.These findings uncover an important mechanism underlying the anti-inflammatory functions of the bacterial fermentation products butyrate and propionate.Dendritic cells (DCs) 2 function as sentinels in peripheral tissues and lymphoid organs guarding against pathogens (1-3). Normally, microorganism-induced immunosuppression is associated with harmful effects in host. In certain cases however, the same process may have beneficial effects on host. Mammalian colon harbors trillions of bacteria without eliciting significant immune activation. There is a mutual beneficial relationship between the gut microbiota and the host (8, 9). The bacterial fermentation products acetate, propionate, and butyrate (collectively called short-chain fatty acids) are believed to be the mediators of the beneficial effects of gut bacteria on the host (10, 11). Among these short-chain fatty acids, butyrate has received the most attention for its biologic effects. The beneficial effects of butyrate on colon range from being a nutrient for colonocytes to being an anti-inflammatory and antitumor agent (12, 13). Although the anti-inflammatory function of butyrate is well known at the phenomenological level, the molecular mechanisms underlying the process are not fully understood.Butyrate is an inhibitor of histone deacetylases (HDACs) (12, 13). The Na ϩ -coupled monocarboxylate transporter SLC5A8 (human ortholog is in uppercase letters, and rodent ortholog is in lowercase letters) is necessary fo...

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“…After stimulation of GM-CSF receptors, signaling pathways are activated through the formation of a unique dodecameric receptor complex (18,19). The transcription factors STAT5 and IFN regulatory factor 4 (IRF4) (20,21) are essential for GM-CSF-mediated signaling pathways, and MAPK and AKT are also activated by GM-CSF (17).…”

Section: Endritic Cells (Dcs) Play a Central Role In Instructing T mentioning

confidence: 99%

Critical Role of AZI2 in GM-CSF–Induced Dendritic Cell Differentiation

Fukasaka

Ori

Kawagoe

et al. 2013

The Journal of Immunology

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TNFR-associated factor family member–associated NF-κB activator (TANK)–binding kinase 1 (TBK1) is critical for the activation of IFN regulatory factor 3 and type I IFN production upon virus infection. A set of TBK1-binding proteins, 5-azacytidine–induced gene 2 (AZI2; also known as NAP1), TANK, and TBK1-binding protein 1 (TBKBP1), have also been implicated in the production of type I IFNs. Among them, TANK was found to be dispensable for the responses against virus infection. However, physiological roles of AZI2 and TBKBP1 have yet to be clarified. In this study, we found that none of these TBK1-binding proteins is critical for type I IFN production in mice. In contrast, AZI2, but not TBKBP1, is critical for the differentiation of conventional dendritic cells (cDCs) from bone marrow cells in response to GM-CSF. AZI2 controls GM-CSF–induced cell cycling of bone marrow cells via TBK1. GM-CSF–derived DCs from AZI2-deficient mice show severe defects in cytokine production and T cell activation both in vitro and in vivo. Reciprocally, overexpression of AZI2 results in efficient generation of cDCs, and the cells show enhanced T cell activation in response to Ag stimulation. Taken together, AZI2 expression is critical for the generation of cDCs by GM-CSF and can potentially be used to increase the efficiency of immunization by cDCs.

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Deacetylase Activity Is Required for STAT5-Dependent GM-CSF Functional Activity in Macrophages and Differentiation to Dendritic Cells

Cited by 49 publications

References 63 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

Blockade of Dendritic Cell Development by Bacterial Fermentation Products Butyrate and Propionate through a Transporter (Slc5a8)-dependent Inhibition of Histone Deacetylases

Critical Role of AZI2 in GM-CSF–Induced Dendritic Cell Differentiation

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