1,25-dihydroxyvitamin D3 Protects against Macrophage-Induced Activation of NFκB and MAPK Signalling and Chemokine Release in Human Adipocytes

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-kappa B (NF kappa B) subunit inhibitor kappa B alpha (I kappa B alpha) (71%, P<0.001) and increased NF kappa B 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 NF kappa B signalling by increasing I kappa Ba expression (2.7-fold, P=0.005) and reducing NF kappa B 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 NF kappa B and MAPK signalling pathways.