Adrenomedullin Regulates<i>IL-1β</i>Gene Expression in F4/80+ Macrophages during Synovial Inflammation

Takano, Shotaro; Uchida, Kentaro; Miyagi, Masayuki; Inoue, Gen; Aikawa, Jun; Iwabuchi, Kazuya; Takaso, Masashi

doi:10.1155/2017/9832430

Cited by 16 publications

(18 citation statements)

References 34 publications

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“…Here, we found that ADM from H. pylori -infected gastric epithelial cells directly promoted T cell proliferation and IFN-γ production. Besides, we also found that ADM indirectly acted on T cells by IL-12 derived by ADM stimulated-macrophages, which resembles the data on IL-1β secretion in synovial inflammation [36]. 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 [37,38].…”

Section: Discussionsupporting

confidence: 74%

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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Section: Discussionsupporting

confidence: 74%

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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“…NGF levels are elevated frequently in inflamed knee joints and have been linked to OA disease progression [15,22,23]. This is evidenced further by findings that NGF production is increased in synovial fibroblasts in the knees of OA patients [11].…”

Section: Discussionmentioning

confidence: 94%

“…Synovial macrophages produce inflammatory cytokines in response to synovial hyperplasia and under OA conditions [12,16,17,23]. Previous studies have also demonstrated an increased number of activated macrophages and IL-1b concentrations in the SYN of a synovial dysplasia mouse model [23].…”

Section: Discussionmentioning

confidence: 96%

“…Synovial macrophages produce inflammatory cytokines in response to synovial hyperplasia and under OA conditions . Previous studies have also demonstrated an increased number of activated macrophages and IL‐1β concentrations in the SYN of a synovial dysplasia mouse model . In addition, STR/Ort mice have higher IL‐1β, TNF‐α and NGF gene expression in their synovium than C57BL/6J mice .…”

Section: Discussionmentioning

confidence: 97%

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Nerve growth factor regulation and production by macrophages in osteoarthritic synovium

Takano

Uchida

Inoue

et al. 2017

Clinical and Experimental Immunology

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Nerve growth factor (NGF) functions to modulate osteoarthritis (OA)-associated pain. Although recent studies suggest that tumour necrosis factor (TNF)-α and interleukin (IL)-1β mediate NGF activity in human synovial fibroblasts, the regulation of NGF expression in human synovial macrophages remains unclear. Here, we examined the role of macrophages in the production and regulation of synovial (SYN) NGF in osteoarthritic knee joints by examining the mRNA expression of TNF-α and IL-1β in freshly isolated CD14-positive (macrophage-rich fraction) and CD14-negative cells (fibroblast-rich fraction) in synovial tissue from OA patients by quantitative polymerase chain reaction. We also examined the effects of IL-1β and TNF-α on NGF mRNA expression in cultured CD14-positive (macrophage-rich fraction) and CD14-negative cells (fibroblast-rich fraction). In addition, to examine the contribution of macrophages to NGF, TNF-α and IL-1β expression, we injected clodronate liposomes systemically into STR/Ort mice, an osteoarthritis animal model, to deplete macrophages. TNF-α and IL-1β mRNA levels in CD14-positive cells from the SYN of OA patients was significantly higher than that in CD14-negative cells, while NGF expression did not differ markedly between the two cell fractions. In addition, treatment of human cultured CD14-positive and -negative cells with IL-1β and TNF-α enhanced NGF mRNA and protein levels. Expression of NGF, IL-1β and TNF-α was also reduced significantly in STR/Ort mice upon macrophage depletion. These findings suggest that IL-1β and TNF-α regulate NGF expression and production in synovial macrophages and fibroblasts in osteoarthritic joints.

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“…Cxcl16 (a chemokine ligand), Cd248 (a transmembrane glycoprotein), Ptx3 (an in ammation induced gene), Fcrl2 (a subtype of Fc receptor-like molecules), Tgfb1i1 (a transforming growth factor beta 1 induced gene), Nostrin (a nitric oxide synthase tra c inducer), Vwf (an adhesive and multimeric glycoprotein), Tnxb (a member of the tenascin family), Ahr (a ligand-activated transcription factor), I t1 (an interferon-induced protein), Il2rb (an interleukin-2 receptor subunit) and Clec9a (a C-type lectin) are involved in the in ammation associated with arthritis pathology [71][72][73][74][75][76][77][78][79][80][81][82]. Ramp3 is a receptor activitymodifying protein that is highly expressed during joint in ammation [83]. Cyp1b1 (a member of the cytochrome P450 enzyme family), Pcsk1n (an inhibitor of prohormone convertase 1), Dlx3 (a family member of homeobox proteins), Nkd2 (a regulator of in ammatory response), Mmp19 (a subtype of matrix metalloproteinases), Htra4 (a subtype of serine proteases), Aplnr (a G protein-coupled receptor of apelin), Tubb2b (a beta isoform of tubulin), Arg1 (a cytosolic manganese-dependent enzyme) and Clic5 (a chloride intracellular channel protein) are reported to be highly expressed under osteoarthritic condition [84][85][86][87][88][89][90][91][92][93].…”

Section: Discussionmentioning

confidence: 99%

Insights Into the Molecular Mechanism of Deer Antler Extract Serving as a Potential Chondroprotective Agent for Articular Cartilage

Yao¹,

Zhou²,

Zhang³

et al. 2020

Preprint

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Background Deer antler is considered as a precious traditional Chinese medicinal material, and has been widely used to reinforce kidney’s yang, nourish essence and strengthen bone function. The most prominent bioactive components in deer antler are water-soluble proteins that play potential roles in bone formation and repair. The aim of this study was to explore the molecular control and therapeutic targets of deer antler extract (DAE) on articular cartilage. Methods DAE was prepared as previously described. All rats were randomly divided into Blank group and DAE group (10 rats per group) after 7-day adaptive feeding. The rats in DAE group were orally administrated with DAE at a dose of 0.2 g/kg per day for 3 weeks and the rats in Blank group were fed with drinking water. Total RNA was isolated from the articular cartilage of knee joints. RNA sequencing (RNA-seq) experiment combined with quantitative real-time polymerase chain reaction (qRT-PCR) verification assay were carried out to explore the molecular control and therapeutic targets of DAE on articular cartilage. Results We demonstrated that DAE played a potential role in promoting cartilage formation, growth and repair, and inhibiting cartilage degeneration and inflammation. These effects were possibly achieved by accelerating the expression of functional genes involved in chondrocyte commitment, survival, proliferation and differentiation, and suppressing the expression of susceptibility genes involved in the pathophysiology of osteoarthritis. Conclusions DAE might serve as a chondroprotective agent for treating cartilage degeneration and inflammation by boosting the ability of cartilage growth and repair. Thus, our findings will contribute towards deepening the knowledge about the molecular control and therapeutic targets of DAE on the treatment of osteoarthritis.

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Adrenomedullin RegulatesIL-1βGene Expression in F4/80+ Macrophages during Synovial Inflammation

Cited by 16 publications

References 34 publications

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

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

Nerve growth factor regulation and production by macrophages in osteoarthritic synovium

Insights Into the Molecular Mechanism of Deer Antler Extract Serving as a Potential Chondroprotective Agent for Articular Cartilage

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