IFN-<i>γ</i>Activates cAMP/PKA/CREB Signaling Pathway in Murine Peritoneal Macrophages

Liu, Lei; Wang, Yun; Fan, Yi; Li, Changlin; Chang, Zongliang

doi:10.1089/107999004323142196

Cited by 27 publications

(20 citation statements)

References 33 publications

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“…Many different signaling modules can activate PKA, including prostaglandins (e.g., PGE 2 ) through the prostanoid receptor ; inflammatory cytokines through interferon signaling (Liu et al, 2004), calcium flux, purinergic ( Jing et al; accompanying paper); and -adrenergic signaling. Because of recent evidence suggesting that PGE 2 is synthesized in response to shear stress (Cherian et al, 2003;Ogawa et al, 2014), and the proposed role of PGE 2 in embryonic hematopoiesis ), PGE 2 is a candidate upstream of PKA for the exploration of shear stress-mediated signaling (Diaz et al; accompanying paper).…”

Section: Discussionmentioning

confidence: 99%

Flow-induced protein kinase A–CREB pathway acts via BMP signaling to promote HSC emergence

Kim¹,

Nakano²,

Das³

et al. 2015

J Cell Biol

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Fluid shear stress promotes the emergence of hematopoietic stem cells (HSCs) in the aortagonad-mesonephros (AGM) of the developing mouse embryo. We determined that the AGM is enriched for expression of targets of protein kinase A (PKA)-cAMP response elementbinding protein (CREB), a pathway activated by fluid shear stress. By analyzing CREB genomic occupancy from chromatin-immunoprecipitation sequencing (ChIP-seq) data, we identified the bone morphogenetic protein (BMP) pathway as a potential regulator of CREB. By chemical modulation of the PKA-CREB and BMP pathways in isolated AGM VEcadherin + cells from mid-gestation embryos, we demonstrate that PKA-CREB regulates hematopoietic engraftment and clonogenicity of hematopoietic progenitors, and is dependent on secreted BMP ligands through the type I BMP receptor. Finally, we observed blunting of this signaling axis using Ncx1-null embryos, which lack a heartbeat and intravascular flow. Collectively, we have identified a novel PKA-CREB-BMP signaling pathway downstream of shear stress that regulates HSC emergence in the AGM via the endothelial-tohematopoietic transition.

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Section: Discussionmentioning

confidence: 99%

Flow-induced protein kinase A–CREB pathway acts via BMP signaling to promote HSC emergence

Kim¹,

Nakano²,

Das³

et al. 2015

J Cell Biol

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“…A STAT binding sequence has been identified in the C/EBP␤ promoter and may explain its expression in monocytes/macrophages in response to IFN-␥. Alternatively, activation of the CREB transcription factor by IFN-␥ may also induce C/EBP␤ expression, as this factor has been implicated in its regulation (35,43). Future studies will determine whether these factors or novel molecules are targets of inhibition by CD46-utilizing Ads.…”

Section: Discussionmentioning

confidence: 99%

CD46-Utilizing Adenoviruses Inhibit C/EBPβ-Dependent Expression of Proinflammatory Cytokines

Iacobelli-Martinez

Nepomuceno

Connolly

et al. 2005

J Virol

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The majority of adenovirus serotypes utilize the coxsackievirus-adenovirus receptor (CAR) for virus-host cell attachment, but subgroup B and subgroup D (adenovirus type 37 [Ad37]) viruses recognize CD46. CD46 is a ubiquitously expressed receptor that serves as a cofactor for the inactivation of the complement components C3b and C4b, and it also serves as a receptor for diverse microbial pathogens. A reported consequence of CD46 engagement is a reduced capability of human immune cells to express interleukin-12 (IL-12), a cytokine involved in both the innate and adaptive immune responses. Studies were thus undertaken to determine whether CD46-utilizing Ads alter the expression of proinflammatory cytokines. Subgroup B (Ad16 and -35) and Ad37, but not Ad2 or -5, significantly reduced IL-12 production by human peripheral blood mononuclear cells stimulated with gamma interferon (IFN-␥) and lipopolysaccharide. IL-12 mRNA (p35 and p40 subunits) levels as well as other cytokine mRNA levels (IL-1␣ and -␤, IL-1Ra, and IL-6) were decreased upon interaction with CD46-utilizing Ads. Analysis of transcription factor activity required for cytokine expression indicated that CD46-utilizing Ads preferentially inhibited IFN-␥-induced C/EBP␤ protein expression, consequently reducing its ability to form DNA complexes. Interference with IFN-␥ signaling events by CD46-utilizing Ads, but not CAR-utilizing Ads, reveals a potentially critical difference in the host immune response against distinct Ad vectors, a situation that has implications for gene delivery and vaccine development.Accumulating knowledge has revealed that virus association with cell receptors may have important consequences beyond simple host cell recognition. For example, human adenovirus (Ad)-receptor interactions trigger multiple signaling pathways, some of which promote cell entry (32-34), while others may provoke acute inflammatory responses (8,18,36,41,(57)(58)(59). Many of the 51 known Ad serotypes classified into subgroups A to F cause acute upper respiratory tract, gastrointestinal, and ocular diseases. Cell tropism is a major factor that influences the pathological consequences of Ad infection. Ad cell entry is initiated by binding of the virus fiber protein to a specific host receptor and is followed by the association of the penton base capsid protein with ␣ v integrins leading to virus internalization (42). While most Ad serotypes use coxsackievirus-adenovirus receptor (CAR) as their primary attachment receptor (6, 60), subgroup B and at least one subgroup D virus use an alternative receptor, CD46 (13,52,55,64).CD46, also known as membrane cofactor protein, is a member of the family of complement regulatory proteins that bind the complement proteins C3b and C4b, serving as a cofactor for their inactivation by a serum protease (53). In addition to certain Ad serotypes, CD46 is a receptor for multiple microbial pathogens, including a gram-negative bacterium, Neisseria sp. (25), the Edmonston strain of measles virus (MV) (12, 40), and human herpesvirus 6 (HHV6...

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“…HCV core protein is not likely to downregulate CREB for C9 inhibition, although IFN-␥ activates cAMP/protein kinase A (PKA)/CREB independently of the Jak-Stat signaling pathway (17). In fact, HCV core protein is known to upregulate CREB phosphorylation in hepatocarcinoma cells (18,19).…”

Section: Downregulation Of C9 In Hcv-infected Patient Samplesmentioning

confidence: 99%

Hepatitis C Virus Suppresses C9 Complement Synthesis and Impairs Membrane Attack Complex Function

Kim

Meyer

Bisceglie

et al. 2013

J Virol

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Hepatitis C virus (HCV) proteins inhibit complement component expression, which may attenuate immunity against infection. In this study, we examined whether HCV regulates the membrane attack complex (MAC) via complement component C9. MAC is composed of C5b to C9 (C5b-9) and mediates cell lysis of invaded pathogens. Liver biopsy specimens from chronically HCVinfected patients exhibited a lower level of C9 mRNA expression than liver biopsy specimens from unrelated disease or healthy control human liver RNA. Hepatocytes infected with cell culture-grown HCV or expressing HCV core protein also displayed significant repression of C9 mRNA and protein levels. Promoter analysis suggested that the T cell factor-4 (TCF-4E) transcription factor is responsible for HCV core-mediated C9 promoter regulation. Sera from chronically HCV-infected patients displayed a lower level of C5b-9 and a reduced antimicrobial effect on model organisms compared to unrelated patient sera or sera from healthy volunteers. Together, these results for C9 regulation by HCV core protein coupled with functional impairment of the membrane attack complex underscore HCV-mediated attenuation of immune mechanisms.

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IFN-γActivates cAMP/PKA/CREB Signaling Pathway in Murine Peritoneal Macrophages

Cited by 27 publications

References 33 publications

Flow-induced protein kinase A–CREB pathway acts via BMP signaling to promote HSC emergence

Flow-induced protein kinase A–CREB pathway acts via BMP signaling to promote HSC emergence

CD46-Utilizing Adenoviruses Inhibit C/EBPβ-Dependent Expression of Proinflammatory Cytokines

Hepatitis C Virus Suppresses C9 Complement Synthesis and Impairs Membrane Attack Complex Function

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