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Vitamin D in inflammatory diseases

Following is another brief/adaptation from the excellent  review article from “Vitamin D in inflammatory diseases”.

Review

Changes in vitamin D serum levels have been associated with inflammatory diseases,such as inflammatory bowel disease (IBD), rheumatoid arthritis, systemic lupus erythematosus, ultiple sclerosis (MS), atherosclerosis, or asthma.

  • Thea K. Wöbke, Bernd L. Sorg and Dieter Steinhilber*
  • Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Frankfurt, Germany.

Genome- and transcriptome-wide studies indicate that vitamin D signaling modulates many inflammatory responses on several levels.

This includes

(i) the regulation of the expression of genes which generate pro-inflammatory ediators, such as cyclooxygenases or 5-lipoxygenase,

(ii) the interference with transcription factors, such as NF-κB, which regulate the expression of inflammatory genes and (iii) the activation of signaling cascades, such as MAP kinases which  mediate inflammatory responses.

Vitamin D targets various tissues and cell types, a number of which belong to the immune system, such as monocytes/macrophages, dendritic cells (DCs) as well as B- and T cells, leading to individual responses of each cell type.

One hallmark of these specific vitamin D effects is the cell-type specific regulation of genes involved in the regulation of inflammatory processes and the interplay between vitamin D signaling and other signaling cascades involved in inflammation.

An important task in the near future will be the elucidation of the regulatory mechanisms that are involved in the regulation of inflammatory responses by vitamin D on the molecular level by the use of techniques such as chromatin immunoprecipitation (ChIP), ChIP-seq, and FAIRE-seq.

Thus, initially considered cartilage driven, OA is a much more complex disease with inflammatory mediators released by cartilage, bone and synovium.

 

CONCLUSIONS

It is well established that 1α,25(OH)2D3 influences cytokine gene expression and signaling in several different cell types.

Firstly, this is the case for the pleiotropic mediator TGF-β, for which it has been shown that either the expression of the cytokine itself or expression of associated signaling components is downregulated by 1α,25(OH)2D3.

In hepatocytes, 1α,25(OH)2D3 has been found to influence TGF-β signaling in a genome wide scale by directing binding of Smad proteins to target genes.

These actions  of 1α,25(OH)2D3 on TGF-β expression or signaling were able to

inhibit fibrosis and associated inflammation.

Second, the interleukins are a vast group of inflammatory cytokines that are clearly regulated by 1α,25(OH)2D3 in a cell-specific manner.

However,for several members of this family (e.g., IL-1, IL-6, and IL-8), both positive or negative regulation by 1α,25(OH)2D3 has been observed.

A closer look at the parameters that determine the outcome of 1α,25(OH)2D3 action on the expression of these genes is warranted.

This applies in particular to the time-scale of changes in gene expression, as different responses may occur during separate stages of 1α,25(OH)2D3 action.

Regarding the mechanisms, recruitment of VDR to the respective genomic regions, as well as interaction of 1α,25(OH)2D3 signaling with other transcription factors involved in IL expression (NFAT, NF-κB, Runx1), seem to occur. Concerning the p38 MAP kinase phosphatase MKP1, it was found that GCR and VDR/RXR act in a synergistic manner to induce MKP1 expression in monocytes.

This results in reduced p38 activation and reduced formation of proinflammatory cytokines. As a further cytokine, the proinflammatory mediator TNFα has been identified as a 1α,25(OH)2D3 target gene.

Also in this case, the vitamin D effects are cell-specific:

With cell samples that mainly contain T-cells, downregulation of TNFα has been observed, whereas for monocytic cells, either positive or negative regulation occurred depending on the differentiation state.

Finally, gene expression of the proinflammatory mediator IFNγ has been described to be suppressed by 1α,25(OH)2D3 in T-cells.

Altogether, the influence of 1α,25(OH)2D3 on the expression of interleukins, TNFα, and IFNγ by different cell types, and the consequences for the cellular interplay that are to be anticipated, amounts to a complex picture. In Figure 3, the influence of 1α,25(OH)2D3 on the expression of these cytokines is summarized for the major immune cells (monocytes, DCs, and different T-cell subsets).

The resulting pattern supports a shift of T-cell responses from a Th1 type toward Th2 reactions and a suppression of Th17 responses.

The effect of 1α,25(OH)2D3 on cytokine expression in antigen presenting cells (monocytes, DCs) remains unclear and seems to depend on the time of stimulation, the differentiation state and other factors.

PERSPECTIVES

Modulation of GCR, NFκB, NFAT as well as SMAD signaling plays a central role in the immunomodulatory activities of 1α,25(OH)2D3. Mechanistic studies on individual genes gave some mechanistic insights into the mechanisms involved in the interaction between VDR/RXR and the above mentioned transcription factors. These mechanisms include competitive binding as well as a crosstalk between the signaling pathways on multiple levels including the promoter level. However, by using ChIP seq and other techniques which allow a genome-wide view, we are just starting to understand the signaling network which is responsible for cell-type-specific and locus-dependent gene activation by ligand-regulated transcription factors such as VDR/RXR.

For example, intersecting VDR/SMAD regulatory circuits have just been unraveled and it was shown that TGFβ signaling facilitates VDR binding to certain gene loci. More such data are required to increase our understanding of the complex gene regulatory network that is affected by 1α,25(OH)2D3. Especially, genome-wide data on VDR loci in conjunction with analyses of other, inflammation-related key transcription factors in different cell types and various stimuli are necessary to understand the complex regulation of gene transcription during inflammation.

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