Anti‐Inflammatory Effects of PEGylated Human Adrenomedullin in a Mouse DSS‐Induced Colitis Model

Nagata, Sayaka; Yamasaki, Motoo; Kïtamura, Kazuo

doi:10.1002/ddr.21383

Cited by 24 publications

(21 citation statements)

References 27 publications

(32 reference statements)

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“…3, C and F), it seems likely that the disulfide does in fact impart a significant affinity increase. The ability to incorporate a disulfide bond into AM2/IMD could be valuable for therapeutic development because it might increase peptide stability in plasma, which is an important consideration for these peptides (54,55).…”

Section: Receptor-bound Adrenomedullin 2/intermedin Conformationmentioning

confidence: 99%

Structure–function analyses reveal a triple β-turn receptor-bound conformation of adrenomedullin 2/intermedin and enable peptide antagonist design

Roehrkasse

Booe

Lee

et al. 2018

Journal of Biological Chemistry

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The cardioprotective vasodilator peptide adrenomedullin 2/intermedin (AM2/IMD) and the related adrenomedullin (AM) and calcitonin gene-related peptide (CGRP) signal through three heterodimeric receptors comprising the calcitonin receptor-like class B G protein-coupled receptor (CLR) and a variable receptor activity-modifying protein (RAMP1, -2, or -3) that determines ligand selectivity. The CGRP receptor (RAMP1:CLR) favors CGRP binding, whereas the AM (RAMP2:CLR) and AM (RAMP3:CLR) receptors favor AM binding. How AM2/IMD binds the receptors and how RAMPs modulate its binding is unknown. Here, we show that AM2/IMD binds the three purified RAMP-CLR extracellular domain (ECD) complexes with a selectivity profile that is distinct from those of CGRP and AM. AM2/IMD bound all three ECD complexes but preferred the CGRP and AM receptor complexes. A 2.05 Å resolution crystal structure of an AM2/IMD antagonist fragment-bound RAMP1-CLR ECD complex revealed that AM2/IMD binds the complex through a unique triple β-turn conformation that was confirmed by peptide and receptor mutagenesis. Comparisons of the receptor-bound conformations of AM2/IMD, AM, and a high-affinity CGRP analog revealed differences that may have implications for biased signaling. Guided by the structure, enhanced-affinity AM2/IMD antagonist variants were developed, including one that discriminates the AM and AM receptors with ∼40-fold difference in affinities and one stabilized by an intramolecular disulfide bond. These results reveal differences in how the three peptides engage the receptors, inform development of AM2/IMD-based pharmacological tools and therapeutics, and provide insights into RAMP modulation of receptor pharmacology.

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Section: Receptor-bound Adrenomedullin 2/intermedin Conformationmentioning

confidence: 99%

Structure–function analyses reveal a triple β-turn receptor-bound conformation of adrenomedullin 2/intermedin and enable peptide antagonist design

Roehrkasse

Booe

Lee

et al. 2018

Journal of Biological Chemistry

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show abstract

“…It will be interesting to see which cell type plays a more important role. It is clear that a mixed acute and chronic inflammatory reaction takes place in H. pylori-induced inflammatory environments, where multifarious immune cell types infiltrate and play complicated roles 16,17,51,52 . In a recent report, TLR9 −/− mice were found to show increased signs of gastritis upon H. pylori infection 53 .…”

Section: Discussionmentioning

confidence: 99%

“…For example, it has been reported that overexpression of ADM in the stomach can inhibit gastric acid secretion 14 . In other studies, ADM protects the mucosa as an endothelial cell growth factor by promoting mucosal healing 15 , and has antiinflammatory effects in a mouse DSS-induced colitis model 16 . However, the relationship between ADM and gastric inflammation, especially in H. pylori-associated gastritis, is presently unknown.…”

Section: Introductionmentioning

confidence: 90%

Helicobacter pylori-induced adrenomedullin modulates IFN-γ-producing T-cell responses and contributes to gastritis

et al. 2020

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Adrenomedullin (ADM) is a multifunctional peptide that is expressed by many surface epithelial cells, but its relevance to Helicobacter pylori (H. pylori)-induced gastritis is unknown. Here, we found that gastric ADM expression was elevated in gastric mucosa of H. pylori-infected patients and mice. In H. pylori-infected human gastric mucosa, ADM expression was positively correlated with the degree of gastritis; accordingly, blockade of ADM resulted in decreased inflammation within the gastric mucosa of H. pylori-infected mice. During H. pylori infection, ADM production was promoted via PI3K-AKT signaling pathway activation by gastric epithelial cells in a cagA-dependent manner, and resulted in increased inflammation within the gastric mucosa. This inflammation was characterized by the increased IFN-γ-producing T cells, whose differentiation was induced via the phosphorylation of AKT and STAT3 by ADM derived from gastric epithelial cells. ADM also induced macrophages to produce IL-12, which promoted the IFN-γ-producing Tcell responses, thereby contributing to the development of H. pylori-associated gastritis. Accordingly, blockade of IFN-γ or knockout of IFN-γ decreased inflammation within the gastric mucosa of H. pylori-infected mice. This study identifies a novel regulatory network involving H. pylori, gastric epithelial cells, ADM, macrophages, T cells, and IFN-γ, which collectively exert a pro-inflammatory effect within the gastric microenvironment.

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“…For example, it has been reported that over-expression of ADM in the stomach can inhibit gastric acid secretion [11]. In other studies, ADM can protect mucosal as an endothelial cell growth factor by promoting mucosal healing [12], and has anti-inflammatory effects in a mouse DSS-induced colitis model [13]. However, the relationship between ADM and gastric inflammation especially in H. pylori -associated gastritis is presently unknown.…”

Section: Introductionmentioning

confidence: 99%

Helicobacter pylori-induced adrenomedullin modulates IFN-γ-producing T-cell responses and contribute to gastritis

Zhuang

Kong

Zhang

et al. 2018

Preprint

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23Abbreviations used in this paper: Helicobacter pylori, H. pylori; adrenomedullin, ADM; interleukin, IL; 24 interferon, IFN; receptor activity modifying protein, RAMP; phosphoinositide 3-kinase, PI3K; signal 25 transducers and activators of transcription, STAT; wild-type, WT; knockout, KO; post infection, p.i.; 26 haematoxylin and eosin, H&E.Abstract 2 Adrenomedullin (ADM) is a multifunctional peptide that is expressed by many surface epithelial cells, 3 but its relevance to H. pylori-induced gastritis is unknown. Here, we found that gastric ADM 4 expression was elevated in gastric mucosa of H. pylori-infected patients and mice. In H. 5 pylori-infected human gastric mucosa, ADM expression was positively correlated with the degree of 6 gastritis, accordingly, blockade of ADM resulted in decreased inflammation within the gastric 7 mucosa of H. pylori-infected mice. During H. pylori infection, ADM production was promoted via 8 PI3K-AKT signaling pathway activation by gastric epithelial cells in a cagA-dependent manner, and 9 resulted in increased inflammation within the gastric mucosa. This inflammation was characterized 10 by the increased IFN-γ-producing T cells, whose differentiation was induced via the phosphorylation 11 of AKT and STAT3 by ADM derived from gastric epithelial cells. ADM also induced macrophages to 12 produce IL-12, which promoted the IFN-γ-producing T-cell responses, thereby contributing to the 13 development of H. pylori-associated gastritis. Accordingly, blockade of IFN-γ or knockout of IFN-γ 14 decreased inflammation within the gastric mucosa of H. pylori-infected mice. This study identifies a 15 novel regulatory network involving H. pylori, gastric epithelial cells, ADM, macrophages, T cells, and 16 IFN-γ, which collectively exert a pro-inflammatory effect within the gastric microenvironment.17 18 Author summary 19 H. pylori infect almost half the world's population. Once infected, most of people carry the bacteria 20 lifelong if left untreated, so that persistent H. pylori infection can lead to chronic gastritis, peptic 21 ulceration and ultimately gastric cancer. H. pylori infection is accompanied with increased 22 inflammation in gastric mucosa, but the mechanisms of chronic gastritis induced by H. pylori 23 infection remains poorly understood. We studied a multifunctional peptide known as adrenomedullin 24 (ADM) in gastric epithelial cells, which was known as a key factor of regulating gastrointestinal 25 physiology and pathology. Here, we found that gastric ADM expression was elevated in gastric 26 mucosa of H. pylori-infected patients and mice, and was positively correlated with the degree of 27 gastritis. ADM production was promoted via PI3K-AKT signaling pathway activation by gastric 28 epithelial cells in a cagA-dependent manner. Blockade of ADM during H. pylori infection resulted in 29 decreased gastric inflammation that was characterized by the increased IFN-γ-producing T cells 30 which was induced via the phosphorylation of AKT and STAT3 by ADM derived from gastric 1 epitheli...

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Anti‐Inflammatory Effects of PEGylated Human Adrenomedullin in a Mouse DSS‐Induced Colitis Model

Cited by 24 publications

References 27 publications

Structure–function analyses reveal a triple β-turn receptor-bound conformation of adrenomedullin 2/intermedin and enable peptide antagonist design

Structure–function analyses reveal a triple β-turn receptor-bound conformation of adrenomedullin 2/intermedin and enable peptide antagonist design

Helicobacter pylori-induced adrenomedullin modulates IFN-γ-producing T-cell responses and contributes to gastritis

Helicobacter pylori-induced adrenomedullin modulates IFN-γ-producing T-cell responses and contribute to gastritis

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