Adrenomedullin and adrenomedullin binding protein-1 downregulate TNF-α in macrophage cell line and rat Kupffer cells

Wu, Rongqian; Zhou, Mian; Wang, Haichao

doi:10.1016/s0167-0115(03)00018-1

Cited by 71 publications

(73 citation statements)

References 35 publications

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“…In addition, serum TNF-α levels were more than 2-fold higher in AM +/− septic mice than in WT septic mice. These observations are consistent with previous reports showing that AM reduces the production of TNF-α in macrophages and Kupffer cells [33].…”

Section: Discussionsupporting

confidence: 94%

“…Many in vitro studies have suggested an important regulatory role for AM in sepsis and other inflammatory diseases [13,18,19,30,33,35]. Moreover, genetic over-expression of AM in the mouse vasculature or therapeutic administration of AM peptide in rats or mice had beneficial effects on reducing the inflammatory and hemodynamic insults elicited by septic shock [28].…”

Section: Discussionmentioning

confidence: 99%

“…When treated with endotoxin, mice over-expressing AM in their vasculature experience less severe hemodynamic and inflammatory responses, less liver damage and lower mortality rates compared to WT endotoxin-treated controls [28]. AM has also been shown to reduce TNF-α expression and release in macrophage cell lines and rat Kupffer cells [33]. More recently, administration of AM to rats with α-toxin-induced sepsis reduced vascular hyperpermeability and resulted in dramatically improved survival rates [31].…”

Section: Introductionmentioning

confidence: 99%

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Mice heterozygous for adrenomedullin exhibit a more extreme inflammatory response to endotoxin-induced septic shock

Dackor

Caron

2007

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Adrenomedullin (AM) is a highly conserved peptide that can act as a potent vasodilator, antimicrobial factor and anti-inflammatory factor. Several studies have implicated diverse roles for AM in regulating the inflammatory and hemodynamic responses to septic shock. Moreover, during sepsis the receptors that mediate AM signaling [calcitonin receptor-like receptor (calcrl) and receptor activity modifying proteins (RAMP) 2 and 3] undergo dynamic and robust changes in their expression. Although numerous studies have used animal models to study the role of administered or increased AM in septic animals, genetic studies to determine the consequences of reduced AM during septic shock have not yet been performed. Here, we used a murine model of lipopolysaccharide (LPS)-induced septic shock to assess the inflammatory response in mice heterozygous for the AM gene. Following LPS challenge, AM +/− mice had higher expression of TNF-α and IL-1β than LPS-treated wild-type (WT) controls. Consequently, serum TNF-α was also significantly elevated in LPS-treated AM +/− mice compared to WT LPS-treated mice. We also observed higher serum levels of liver enzymes, suggesting more advanced end-organ damage in mice with genetically reduced AM. Finally, we found that RAMP2 and calcrl expression levels were markedly reduced in LPS-treated mice, whereas RAMP3 expression was significantly elevated. Importantly, these changes in receptor gene expression were conserved in AM +/− mice, demonstrating that AM peptide itself does not impact directly on the expression of the genes encoding its receptors. We therefore conclude that during septic shock the dynamic modulation of AM and its receptors primarily functions to dampen the inflammatory response.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mice heterozygous for adrenomedullin exhibit a more extreme inflammatory response to endotoxin-induced septic shock

Dackor

Caron

2007

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“…Rat KCs were isolated from 6-to 8-week-old normal male Sprague-Dawley rats by collagenase perfusion of the liver, isopycnic sedimentation in a Percoll gradient, and selective adherence (14). The viability of KCs was >95% and the purity of KCs was >85%.…”

Section: Methodsmentioning

confidence: 99%

Suppression of hepatocyte CYP1A2 expression by Kupffer cells via AhR pathway: The central role of proinflammatory cytokines

Cui²,

Dong³

et al. 2006

Int J Mol Med

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Abstract. The hepatic cytochrome P-450 (CYP) enzyme system provides a major aspect of liver function, yet alterations of CYP in sepsis remain largely unknown. Although we have recently shown that CYP1A2, one of the major isoforms of CYP in rats, is downregulated in sepsis, the underlying mechanism and possible therapeutic approaches warrant further investigation. The aim of this study was to determine whether Kupffer cells (KCs) play any role in suppressing CYP1A2 in the hepatocytes (HCs) and if so, how to modulate CYP1A2 expression in sepsis. To study this, primary KCs and HCs were cultured separately or together with or without transwells. Cells and supernatant samples were collected after various stimulations. Additionally, polymicrobial sepsis was induced in rats by cecal ligation and puncture (CLP) with or without curcumin pre-treatment. Liver samples were harvested 20 h post-CLP. The results show that lipopolysaccharide (LPS) did not suppress CYP1A2 in HC or HC/KC coculture with transwells. However, LPS downregulated CYP1A2, aryl hydrocarbon receptor (AhR, a nuclear receptor) and AhR nuclear translocator (Arnt) in coculture without transwells. Anti-TNF-· and anti-IL-1ß antibodies attenuated this downregulation. Moreover, elevated hepatic levels of TNF-· and IL-1ß post-CLP were decreased by curcumin pretreatment. This reduction was associated with increased expression of AhR and CYP1A2. These results indicate that KCs-derived proinflammatory cytokines may play an important role in downregulating CYP1A2 in sepsis. The reduction of AhR/Arnt may be the underlying mechanism for such downregulation. Inhibition of proinflammatory cytokines by curcumin may provide a novel approach to modulate the hepatic CYP function in sepsis.

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“…15a). It has been reported that ADM suppressed the secretion of TNF from lipopolysaccharide-stimulated RAW 264.7 macrophages and NR8383 macrophages (Wong et al, 2005;Kubo et al, 1998;Wu et al, 2003). Because the major source of TNF in inflamed synovial tissue of RA is due to macrophages (Chu et al, 1991) it is plausible that ADM suppresses the production of TNF from activated macrophages in inflamed synovial tissue.…”

Section: Therapeutic Efficacy Of Adm Injection To the Knee In Aia In mentioning

confidence: 99%

Role of Adrenomedullin in Patients with Rheumatoid Arthritis

Chosa¹,

Hamada²,

Ohkura³

2012

Rheumatoid Arthritis - Treatment

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Adrenomedullin and adrenomedullin binding protein-1 downregulate TNF-α in macrophage cell line and rat Kupffer cells

Cited by 71 publications

References 35 publications

Mice heterozygous for adrenomedullin exhibit a more extreme inflammatory response to endotoxin-induced septic shock

Mice heterozygous for adrenomedullin exhibit a more extreme inflammatory response to endotoxin-induced septic shock

Suppression of hepatocyte CYP1A2 expression by Kupffer cells via AhR pathway: The central role of proinflammatory cytokines

Role of Adrenomedullin in Patients with Rheumatoid Arthritis

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