1,25-Dihydroxyvitamin D Promotes Negative Feedback Regulation of TLR Signaling via Targeting MicroRNA-155–SOCS1 in Macrophages

Abstract

The negative feedback mechanism is essential to maintain effective immunity and tissue homeostasis. 1,25-dihydroxyvitamin D (1,25(OH)2D3) modulates innate immune response, but the mechanism remains poorly understood. Here we report that vitamin D receptor (VDR) signaling attenuates Toll-like receptor-mediated inflammation by enhancing the negative feedback inhibition. VDR inactivation leads to hyper inflammatory response in mice and macrophage cultures when challenged with lipopolysaccharide (LPS), due to miR-155 overproduction that excessively suppresses SOCS1, a key regulator that enhances the negative feedback loop. Deletion of miR-155 attenuates vitamin D suppression of LPS-induced inflammation, confirming that 1,25(OH)2D3 stimulates SOCS1 by down-regulating miR-155. 1,25(OH)2D3 down-regulates bic transcription by inhibiting NF-κB activation, which is mediated by a κB cis-DNA element located within the first intron of the bic gene. Together these data identify a novel regulatory mechanism for vitamin D to control innate immunity.

Intestinal epithelial vitamin D receptor signaling inhibits experimental colitis

“…Transfection of IKKβ dramatically induced the luciferase activity of the WT reporter, but not of the mutant reporter, and this induction was also markedly abrogated by 1,25(OH) 2 D 3 ( Figure 9F). Moreover, IKK kinase assays demonstrated that 1,25(OH) 2 D 3 blocked TNF-α-induced IKK activity to phosphorylate IκBα in HCT116 cells ( Figure 9G), confirming our previous finding that 1,25(OH) 2 D 3 /VDR signaling is able to block NF-κB activation (52)(53)(54). To verify that 1,25(OH) 2 D 3 downregulates PUMA by targeting NF-κB activation, we transfected HCT116 cells with an HA-IKKβ-expressing plasmid.…”

“…Briefly, lysates prepared from HCT116 cells or colonic mucosa were immunoprecipitated with anti-IKKγ antibodies (Santa Cruz Biotechnology Inc.). The precipitant was incubated with recombinant GST-IκBα (amino acids 1-54; Clontech) in the presence of γ-32 P-ATP, and 32 P-labeled GST-IκBα (amino acids 1-54) was detected by autoradiography as described previously (58).…”

MicroRNA-15b Modulates Japanese Encephalitis Virus–Mediated Inflammation via Targeting RNF125

“…TLR4-mediated activation of NF-kB induces a negative feedback by upregulating miR-21 and miR-146, which ultimately dampen TLR-induced signaling and cytokine expression (22). In contrast, miR-155 shows anti-and proinflammatory effects by regulating TAB2 and SOCS1, respectively (23,24). Although these miRNAs are associated with fine-tuned inflammatory responses, miRNA-mediated regulation of neuroinflammation during viral infection has not been investigated in detail.…”

Clinical Evaluation of Potential Anti-Inflammatory Effect of Vitamin D3 Adjuvant Therapy for Chronic Asthma in Iraqi Patients

“…In macrophages, the active form of vitamin D (1,25(OH)2D3) cause a reduction of gene expression and protein release of proinflammatory mediators, such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and monocyte chemo attractant protein-1 (MCP-1), result in reduction of monocytes/macrophages recruitment and overall inflammation within tissue [11][12][13].…”