Open Access1,25-dihydroxyvitamin D3 Protects against Macrophage-Induced Activation of NFκB and MAPK Signalling and Chemokine Release in Human Adipocytes
Author(s) -
Cherlyn Ding,
John Wilding,
Bing Chen
Publication year - 2013
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0061707
Subject(s) - chemokine , proinflammatory cytokine , endocrinology , medicine , p38 mitogen activated protein kinases , adipose tissue , mapk/erk pathway , inflammation , downregulation and upregulation , protein kinase a , chemistry , nf κb , iκbα , macrophage , kinase , biology , biochemistry , in vitro , gene
Increased accumulation of macrophages in adipose tissue in obesity is linked to low-grade chronic inflammation, and associated with features of metabolic syndrome. Vitamin D 3 may have immunoregulatory effects and reduce adipose tissue inflammation, although the molecular mechanisms remain to be established. This study investigated the effects of vitamin D 3 on macrophage-elicited inflammatory responses in cultured human adipocytes, particularly the signalling pathways involved. Macrophage-conditioned (MC) medium (25% with adipocyte maintenance media) markedly inhibited protein expression of the nuclear factor-κB (NFκB) subunit inhibitor κBα (IκBα) (71%, P <0.001) and increased NFκB p65 (1.5-fold, P = 0.026) compared with controls. Treatment with 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) abolished macrophage-induced activation of NFκB signalling by increasing IκBα expression (2.7-fold, P = 0.005) and reducing NFκB p65 phosphorylation (68%; P <0.001). The mitogen-activated protein kinase (MAPK) signalling was activated by MC medium, which was also blunted by 1,25(OH) 2 D 3 with a downregulation of phosphorylated p38 MAPK (32%, P = 0.005) and phosphorylated Erk1/2 (49%, P = 0.001). Furthermore, MC medium (12.5% or 25%) dose-dependently upregulated secretion of key proinflammatory chemokines/cytokines (22-368-fold; all P <0.001) and this was significantly decreased by 1,25(OH) 2 D 3 : IL-8 (61% and 31%, P <0.001), MCP-1 (37%, P <0.001 and 36%, P = 0.002), RANTES (78% and 62%, P <0.001) and IL-6 (29%, P <0.001 and 34%, P = 0.019). Monocyte migration-elicited by adipocytes treated with 1,25(OH) 2 D 3 was also reduced (up to 25%, P <0.001). In conclusion, vitamin D 3 could be anti-inflammatory in adipose tissue, decreasing macrophage-induced release of chemokines and cytokines by adipocytes and the chemotaxis of monocytes. Our data suggests these effects are mediated by inhibition of the NFκB and MAPK signalling pathways.