The 1α,25(OH)2D3 Analogs ZK159222 and ZK191784 Show Anti-Inflammatory Properties in Macrophage-Induced Preadipocytes via Modulating the NF-κB and MAPK Signaling

The 1α,25(OH)2D3 Analogs ZK159222 and ZK191784 Show Anti-Inflammatory Properties in Macrophage-Induced Preadipocytes via Modulating the NF-κB and MAPK Signaling

Jingjing Zhu,1,2 John PH Wilding2,3 1Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China; 2Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, Merseyside, UK; 3Clinical Scienc...

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Autores principales: Zhu J, Wilding JPH
Formato: article
Lenguaje:EN
Publicado: Dove Medical Press 2020
Materias:
vitamin d
metaflammatory response
rela
p44/42
p38
Specialties of internal medicine
RC581-951
Acceso en línea:https://doaj.org/article/32554805016449baaa2ba7fae8670012
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spelling oai:doaj.org-article:32554805016449baaa2ba7fae86700122021-12-02T11:37:07ZThe 1α,25(OH)2D3 Analogs ZK159222 and ZK191784 Show Anti-Inflammatory Properties in Macrophage-Induced Preadipocytes via Modulating the NF-κB and MAPK Signaling1178-7007https://doaj.org/article/32554805016449baaa2ba7fae86700122020-05-01T00:00:00Zhttps://www.dovepress.com/the-1alpha25oh2d3-analogs-zk159222-and-zk191784-show-anti-inflammatory-peer-reviewed-article-DMSOhttps://doaj.org/toc/1178-7007Jingjing Zhu,1,2 John PH Wilding2,3 1Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China; 2Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, Merseyside, UK; 3Clinical Sciences Centre, University Hospital Aintree, Liverpool, Merseyside, UKCorrespondence: John PH Wilding Tel +44 151 529 5885Fax +44 151 529 5888Email j.p.h.wilding@liverpool.ac.ukPurpose: Key research findings suggest that attenuating metaflammation in adipose tissue might be a strategic step to prevent the metabolic syndrome and its associated disease outcomes. The anti-inflammatory effects of 1α,25(OH)2D3 have been confirmed in our previous studies, but adverse effects induced at high concentrations restrict its potential clinical translation. Two synthetic 1α,25(OH)2D3 analogs ZK159222 and ZK191784 have manifested promising tissue-specific immunomodulatory actions, but limited data are available on adipose tissue. Hence, in this study, we investigated whether ZK159222 and ZK191784 act on preadipocytes or macrophages to attenuate metaflammatory responses via modulating inflammatory and metabolic signaling in macrophage-induced preadipocytes.Methods: Preadipocyte-specific effects of ZK159222 and ZK191784 on macrophage-induced preadipocytes were tested by pre-incubating and incubating preadipocytes with the analogs and MacCM. Separately, macrophage-specific effects of both analogs on macrophage-induced preadipocytes were tested by incubating preadipocytes with analog-MacCM or MacCM. The effects of 1α,25(OH)2D3 were also examined and set as the positive control. Metaflammatory responses were determined as the concentrations and gene expression of major pro-inflammatory cytokines including IL-1β, IL-6, IL-8, MCP-1 and RANTES, measured using ELISA and qPCR. Inflammatory and metabolic signaling including NF-κB and MAPK were probed using Western blotting.Results: ZK159222 and ZK191784 act on preadipocytes and macrophages to decrease the secretion and gene expression of the major pro-inflammatory cytokines in macrophage-induced preadipocytes. The anti-inflammatory effects were at least as potent as 1α,25(OH)2D3, and no preadipocyte apoptosis was induced at high concentrations. In addition, mostly at high concentrations, both analogs moderately decreased the phosphorylation of relA, p44/42 and p38 MAPK in macrophage-induced preadipocytes.Conclusion: ZK159222 and ZK191784 act on macrophages and preadipocytes to attenuate metaflammatory responses in macrophage-induced preadipocytes, by decreasing phosphorylation of relA/NF-κB, p44/42 and p38 MAPK.Keywords: vitamin D, metaflammatory response, relA, p44/42, p38Zhu JWilding JPHDove Medical Pressarticlevitamin dmetaflammatory responserelap44/42p38Specialties of internal medicineRC581-951ENDiabetes, Metabolic Syndrome and Obesity: Targets and Therapy, Vol Volume 13, Pp 1715-1724 (2020)
institution DOAJ
collection DOAJ
language EN
topic vitamin d
metaflammatory response
rela
p44/42
p38
Specialties of internal medicine
RC581-951
spellingShingle vitamin d
metaflammatory response
rela
p44/42
p38
Specialties of internal medicine
RC581-951
Zhu J
Wilding JPH
The 1α,25(OH)2D3 Analogs ZK159222 and ZK191784 Show Anti-Inflammatory Properties in Macrophage-Induced Preadipocytes via Modulating the NF-κB and MAPK Signaling
description Jingjing Zhu,1,2 John PH Wilding2,3 1Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China; 2Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, Merseyside, UK; 3Clinical Sciences Centre, University Hospital Aintree, Liverpool, Merseyside, UKCorrespondence: John PH Wilding Tel +44 151 529 5885Fax +44 151 529 5888Email j.p.h.wilding@liverpool.ac.ukPurpose: Key research findings suggest that attenuating metaflammation in adipose tissue might be a strategic step to prevent the metabolic syndrome and its associated disease outcomes. The anti-inflammatory effects of 1α,25(OH)2D3 have been confirmed in our previous studies, but adverse effects induced at high concentrations restrict its potential clinical translation. Two synthetic 1α,25(OH)2D3 analogs ZK159222 and ZK191784 have manifested promising tissue-specific immunomodulatory actions, but limited data are available on adipose tissue. Hence, in this study, we investigated whether ZK159222 and ZK191784 act on preadipocytes or macrophages to attenuate metaflammatory responses via modulating inflammatory and metabolic signaling in macrophage-induced preadipocytes.Methods: Preadipocyte-specific effects of ZK159222 and ZK191784 on macrophage-induced preadipocytes were tested by pre-incubating and incubating preadipocytes with the analogs and MacCM. Separately, macrophage-specific effects of both analogs on macrophage-induced preadipocytes were tested by incubating preadipocytes with analog-MacCM or MacCM. The effects of 1α,25(OH)2D3 were also examined and set as the positive control. Metaflammatory responses were determined as the concentrations and gene expression of major pro-inflammatory cytokines including IL-1β, IL-6, IL-8, MCP-1 and RANTES, measured using ELISA and qPCR. Inflammatory and metabolic signaling including NF-κB and MAPK were probed using Western blotting.Results: ZK159222 and ZK191784 act on preadipocytes and macrophages to decrease the secretion and gene expression of the major pro-inflammatory cytokines in macrophage-induced preadipocytes. The anti-inflammatory effects were at least as potent as 1α,25(OH)2D3, and no preadipocyte apoptosis was induced at high concentrations. In addition, mostly at high concentrations, both analogs moderately decreased the phosphorylation of relA, p44/42 and p38 MAPK in macrophage-induced preadipocytes.Conclusion: ZK159222 and ZK191784 act on macrophages and preadipocytes to attenuate metaflammatory responses in macrophage-induced preadipocytes, by decreasing phosphorylation of relA/NF-κB, p44/42 and p38 MAPK.Keywords: vitamin D, metaflammatory response, relA, p44/42, p38
format article
author Zhu J
Wilding JPH
author_facet Zhu J
Wilding JPH
author_sort Zhu J
title The 1α,25(OH)2D3 Analogs ZK159222 and ZK191784 Show Anti-Inflammatory Properties in Macrophage-Induced Preadipocytes via Modulating the NF-κB and MAPK Signaling
title_short The 1α,25(OH)2D3 Analogs ZK159222 and ZK191784 Show Anti-Inflammatory Properties in Macrophage-Induced Preadipocytes via Modulating the NF-κB and MAPK Signaling
title_full The 1α,25(OH)2D3 Analogs ZK159222 and ZK191784 Show Anti-Inflammatory Properties in Macrophage-Induced Preadipocytes via Modulating the NF-κB and MAPK Signaling
title_fullStr The 1α,25(OH)2D3 Analogs ZK159222 and ZK191784 Show Anti-Inflammatory Properties in Macrophage-Induced Preadipocytes via Modulating the NF-κB and MAPK Signaling
title_full_unstemmed The 1α,25(OH)2D3 Analogs ZK159222 and ZK191784 Show Anti-Inflammatory Properties in Macrophage-Induced Preadipocytes via Modulating the NF-κB and MAPK Signaling
title_sort 1α,25(oh)2d3 analogs zk159222 and zk191784 show anti-inflammatory properties in macrophage-induced preadipocytes via modulating the nf-κb and mapk signaling
publisher Dove Medical Press
publishDate 2020
url https://doaj.org/article/32554805016449baaa2ba7fae8670012
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