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Histamine up-regulates oncostatin M expression in human M1 macrophages.

ABSTRACT: BACKGROUND AND PURPOSE:Human monocyte-derived M1 macrophages develop in relation to growth factors, bacterial products, and cytokines in a local micro-environment. M1 macrophages produce pro-inflammatory mediators, in particular, oncostatin M (OSM), which is secreted from the cells in response to the active complement component C5a. As C5a also releases histamine from human mast cells and shows immune modulatory functions similar to histamine in regulating expression of the IL-12 cytokine family, we investigated the effects of histamine on OSM expression in human M1 macrophages. EXPERIMENTAL APPROACH:Cytokine expression was analysed by real-time quantitative PCR and elisa techniques. Normal human epidermal keratinocytes were stimulated with supernatants from activated M1 macrophages, and phosphorylation of STAT3 was assessed by flow cytometry. KEY RESULTS:OSM mRNA expression was highly up-regulated by histamine and agonists targeting the histamine H1 H2 , and H4 receptors in human M1 macrophages and by C5a, which was used as control stimulus. Protein levels of OSM and IL-6 were up-regulated by histamine. Supernatants from histamine-stimulated, fully differentiated M1 macrophages were able to phosphorylate STAT3 in normal human epidermal keratinocytes. CONCLUSIONS AND IMPLICATIONS:The up-regulation of OSM expression in response to histamine and C5a shown in this study provides further evidence that histamine and C5a, acting through their GPCRs, have almost equal functional effects in cells of the monocyte lineage. Both mediators OSM and IL-6 have the capability to activate human keratinocytes. This effect may have an influence on the course of inflammatory skin diseases. LINKED ARTICLES:This article is part of a themed section on New Uses for 21st Century. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.3/issuetoc.

SUBMITTER: Mommert S

PROVIDER: S-EPMC7012943 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Histamine up-regulates oncostatin M expression in human M1 macrophages.

Mommert Susanne S Hüer Marius M Schaper-Gerhardt Katrin K Gutzmer Ralf R Werfel Thomas T

British journal of pharmacology 20191211 3

<h4>Background and purpose</h4>Human monocyte-derived M1 macrophages develop in relation to growth factors, bacterial products, and cytokines in a local micro-environment. M1 macrophages produce pro-inflammatory mediators, in particular, oncostatin M (OSM), which is secreted from the cells in response to the active complement component C5a. As C5a also releases histamine from human mast cells and shows immune modulatory functions similar to histamine in regulating expression of the IL-12 cytokin ...[more]

PMID: 31328788

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Project description:BackgroundPituitary adenylate cyclase-activating polypeptide (PACAP) acts as an anti-atherogenic neuropeptide and plays an important role in cytoprotective, as well as inflammatory processes, and cardiovascular regulation. Therefore, the aim of this study is to investigate the regulatory effects of PACAP and its receptor VPAC1 in relation to inflammatory processes and lipid homeostasis in different macrophage (MΦ) subtypes.MethodsTo investigate the role of PACAP deficiency in the pathogenesis of atherosclerosis under standard chow (SC) or cholesterol-enriched diet (CED) in vivo, PACAP-/- mice were crossbred with ApoE-/- to generate PACAP-/-/ApoE-/- mice. Lumen stenosis in the aortic arch and different MΦ-subtypes were analyzed in atherosclerotic plaques by quantitative immunohistochemistry. Undifferentiated bone marrow-derived cells (BMDC) from 30-weeks-old ApoE-/- and PACAP-/-/ApoE-/- mice were isolated, differentiated into BMDM1- and BMDM2-MΦ, and incubated with oxidized low-density lipoprotein (oxLDL). In addition, PMA-differentiated human THP-1 MΦ were further differentiated into M1-/M2-MΦ and subsequently treated with PACAP38, the VPAC1 agonist [(Ala11,22,28)VIP], the antagonist (PG 97-269), and/or oxLDL. Uptake/accumulation of oxLDL was analyzed by oxLDL-DyLight™488 and Bodipy™ 493/503. The mRNA expression was analyzed by qRT-PCR, protein levels by Western blot, and cytokine release by ELISA.ResultsIn vivo, after 30 weeks of SC, PACAP-/-/ApoE-/- mice showed increased lumen stenosis compared with ApoE-/- mice. In atherosclerotic plaques of PACAP-/-/ApoE-/- mice under CED, immunoreactive areas of VPAC1, CD86, and CD163 were increased compared with ApoE-/- mice. In vitro, VPAC1 protein levels were increased in PACAP-/-/ApoE-/- BMDM compared with ApoE-/- BMDM, resulting in increased TNF-α mRNA expression in BMDM1-MΦ and decreased TNF-α release in BMDM2-MΦ. Concerning lipid homeostasis, PACAP deficiency decreased the area of lipid droplets in BMDM1-/M2-MΦ with concomitant increasing adipose differentiation-related protein level. In THP-1 M1-/M2-MΦ, the VPAC1 antagonist increased the uptake of oxLDL, whereas the VPAC1 agonist decreased the oxLDL-induced intracellular triglyceride content.ConclusionOur data suggest that PACAP via VPAC1 signaling plays an important regulatory role in inflammatory processes in atherosclerotic plaques and in lipid homeostasis in different MΦ-subtypes, thereby affecting foam cell formation. Therefore, VPAC1 agonists or PACAP may represent a new class of anti-atherogenic therapeutics.

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Histamine up-regulates oncostatin M expression in human M1 macrophages.

Publications

Histamine up-regulates oncostatin M expression in human M1 macrophages.

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