Novel insights into biological roles of inducible cAMP early repressor ICER

Režen, Tadeja; Zmrzljak, Uršula Prosenc; Bensa, Tjaša; Tomaš, Tanja Cvitanović; Cirnski, Katarina; Stojan, Jure; Rozman, Damjana

doi:10.1016/j.bbrc.2020.05.017

Cited by 3 publications

(4 citation statements)

References 42 publications

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“…ICER is a major suppressor of the cAMP-PKA-CREB pathway ( 19 ), which can otherwise be activated by FSK ( 15 ). To study whether ICER is involved in reduced synergy between butyrate and higher concentrations of FSK observed earlier in both cell culture ( Figure 2A ) and live animals ( Figures 3A,B ), HD11 cells were treated for various times with 2 mM butyrate and two different concentrations of FSK (5 and 200 μM) individually or in combination.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, we have revealed a negative feedback mechanism involved in diminished HDP induction in response to higher concentrations of FSK with or without butyrate. ICER is transcriptionally induced by activation of the cAMP-PKA-CREB signaling pathway and serves as a major negative feedback mechanism to suppress gene transcription by competing with CREB for the same CRE region of the target gene promoter ( 19 ). We have found that ICER is quickly induced within 1 h, peaked at 3 h, and greatly subdued at 24 h in response to FSK or the FSK/butyrate combination, but higher concentrations of FSK keep ICER expression elevated even after 24 h, which is presumably responsible for reduced HDP gene expression.…”

Section: Discussionmentioning

confidence: 99%

“…FSK-mediated HDP gene induction is believed to transduce through the cAMP-PKA signaling pathway ( 17 , 18 ). It is well-known that a negative feedback loop exists for the cAMP-PKA pathway through upregulation of inducible cAMP early repressors (ICER) that represent a group of smaller proteins transcribed alternatively from the CRE modulator ( CREM ) gene ( 19 ). ICER suppresses gene transcription targeted by the cAMP-PKA-CREB pathway by competing with CREB for the CRE region of target gene promoters ( 19 ).…”

Section: Introductionmentioning

confidence: 99%

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Butyrate and Forskolin Augment Host Defense, Barrier Function, and Disease Resistance Without Eliciting Inflammation

Robinson

Zhang

et al. 2021

Front. Nutr.

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Host defense peptides (HDPs) are an integral part of the innate immune system with both antimicrobial and immunomodulatory activities. Induction of endogenous HDP synthesis is being actively explored as an antibiotic-alternative approach to disease control and prevention. Butyrate, a short-chain fatty acid, and forskolin, a phytochemical, have been shown separately to induce HDP gene expression in human cells. Here, we investigated the ability of butyrate and forskolin to induce the expressions of chicken HDP genes and the genes involved in barrier function such as mucin 2 and claudin 1 both in vitro and in vivo. We further evaluated their efficacy in protecting chickens from Clostridium perfringens-induced necrotic enteritis. Additionally, we profiled the transcriptome and global phosphorylation of chicken HD11 macrophage cells in response to butyrate and forskolin using RNA sequencing and a kinome peptide array, respectively. Our results showed a strong synergy between butyrate and forskolin in inducing the expressions of several, but not all, HDP genes. Importantly, dietary supplementation of butyrate and a forskolin-containing plant extract resulted in significant alleviation of intestinal lesions and the C. perfringens colonization in a synergistic manner in a chicken model of necrotic enteritis. RNA sequencing revealed a preferential increase in HDP and barrier function genes with no induction of proinflammatory cytokines in response to butyrate and forskolin. The antiinflammatory and barrier protective properties of butyrate and forskolin were further confirmed by the kinome peptide array. Moreover, we demonstrated an involvement of inducible cAMP early repressor (ICER)-mediated negative feedback in HDP induction by butyrate and forskolin. Overall, these results highlight a potential for developing butyrate and forskolin, two natural products, as novel antibiotic alternatives to enhance intestinal health and disease resistance in poultry and other animals.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Butyrate and Forskolin Augment Host Defense, Barrier Function, and Disease Resistance Without Eliciting Inflammation

Robinson

Zhang

et al. 2021

Front. Nutr.

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“…One possible reason for HDP induction in response to the MEK1/2 blockage could be due to reduced phosphorylation of cAMP response element-binding protein (CREB), which is a major target of the MEK1/2 pathway ( 49 , 50 ). Reduced CREB phosphorylation in turn suppresses the synthesis of inducible cAMP early repressor (ICER), which could otherwise compete with CREB for the cAMP response element (CRE) on an HDP gene promoter resulting in reduced gene transcription ( 51 , 52 ).…”

Section: Discussionmentioning

confidence: 99%

Natural Cyclooxygenase-2 Inhibitors Synergize With Butyrate to Augment Chicken Host Defense Peptide Gene Expression

Burkardt¹,

Sunkara²,

Xiao³

et al. 2022

Front. Immunol.

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Enhancing the synthesis of microbicidal and immunomodulatory host defense peptides (HDP) is a promising host-directed antimicrobial strategy to combat a growing threat of antimicrobial resistance. Here we investigated the effect of several natural cyclooxygenase-2 (COX-2) inhibitors on chicken HDP gene regulation. Our results indicated that phenolic COX-2 inhibitors such as quercetin, resveratrol, epigallocatechin gallate, anacardic acid, and garcinol enhanced HDP gene expression in chicken HTC macrophage cell line and peripheral blood mononuclear cells (PBMCs). Moreover, these natural COX-2 inhibitors showed a strong synergy with butyrate in augmenting the expressions of multiple HDP genes in HTC cells and PBMCs. Additionally, quercetin and butyrate synergistically promoted the expressions of mucin-2 and claudin-1, two major genes involved in barrier function, while suppressing lipopolysaccharide-triggered interleukin-1β expression in HTC macrophages. Mechanistically, we revealed that NF-κB, p38 mitogen-activated protein kinase, and cyclic adenosine monophosphate signaling pathways were all involved in the avian β-defensin 9 gene induction, but histone H4 was not hyperacetylated in response to a combination of butyrate and quercetin. Because of their HDP-inducing, barrier-protective, and antiinflammatory activities, these natural COX-2 inhibitors, when combined with butyrate, may be developed as novel host-directed antimicrobial therapeutics.

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