calcitriol and Dermatitis--Contact

Low-dose UV radiation (UVR) inhibits the induction of contact hypersensitivity and induces regulatory T cells (Tregs), which because of their antigen specificity harbor therapeutic potential. Topical application of 1α,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) is known to induce Tregs as well, which implies that 1,25(OH)(2)D(3) might be involved in UVR-induced immunosuppression. It was the aim of this study to clarify this issue, to further characterize 1,25(OH)(2)D(3)-induced Tregs and to determine whether they differ from UVR-induced Tregs. Our data demonstrate that 1,25(OH)(2)D(3)-induced Tregs act in an antigen-specific manner and belong to the Foxp3-expressing subtype of Tregs as demonstrated by diphtheria toxin (DT)-mediated depletion of Foxp3(+) Tregs in DEREG (depletion of Tregs) mice. Using Langerin-DTR (DT receptor) knock-in mice, it was shown that Langerhans cells (LCs) are required for the induction of Tregs by 1,25(OH)(2)D(3), as depletion of LCs but not Langerin(+) dermal dendritic cells abrogated the induction of Tregs. Taken together, 1,25(OH)(2)D(3) affects the immune system in a similar manner as UVR, probably using the same pathways. However, vitamin D receptor knockout mice were equally susceptible to UVR-induced immunosupppression as wild-type controls. This indicates that 1,25(OH)(2)D(3) exerts similar immunosuppressive effects as UVR but is dispensable for local UVR-induced immunosuppression.

Topics: Administration, Topical; Adoptive Transfer; Animals; Antigens, Surface; Dermatitis, Contact; Female; Forkhead Transcription Factors; Immunosuppressive Agents; Lectins, C-Type; Mannose-Binding Lectins; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Calcitriol; T-Lymphocytes, Regulatory; Ultraviolet Rays; Ultraviolet Therapy; Vitamin D

UVB radiation stimulates the production of vitamin D and also has immunosuppressive effects. Vitamin D is also known to alter immunological function. Thus, a relevant question is whether vitamin D is a mediator of the immunological effects of UVB. In this issue, Schwarz et al. have addressed this issue and have concluded that although vitamin D has similar effects to UVB on the immune system, UVB-induced immunosuppression can be achieved without the requirement for vitamin D action.

Topics: Animals; Dermatitis, Contact; Female; Immunosuppressive Agents; Ultraviolet Therapy; Vitamin D

1α,25-Dihydroxyvitamin D(3) (1,25D3), the active form of vitamin D(3), is an immunoregulatory hormone with beneficial effects on Th1 cell-mediated inflammatory diseases. Although IL-17-producing CD4(+) T helper (Th17) cells have been recently identified as novel effector cells, the immunomodulating effects of 1,25D3 on Th17 cells have not been well defined. We confirmed here that 1,25D3 inhibited the generation of Th17 cells in vitro. Interestingly, 1,25D3 synergistically suppressed the generation of Th17 cells by the combination with all-trans retinoic acid (ATRA). 1,25D3 and ATRA suppressed the development of allergen-induced contact hypersensitivity (CHS) in a mouse ear swelling model. In addition, we found that 1,25D3 and ATRA significantly inhibited the development of human Th17 cells from both naïve and memory human CD4(+) T cells. 1,25D3 and ATRA effectively suppressed mRNA expressions of IL-1R1, IL-21R, IL-23R, RORC, and AHR in human T cells. ATRA further suppressed IL-6R, whereas 1,25D3 did not. Finally, we found that 1,25D3 and ATRA remarkably blocked IL-22 as well as IL-17 mRNA expression in human memory CD4(+) T cells. Thus, we initially reveal that 1,25D3 and ATRA have synergistic effects on the generation of Th17 cells, suggesting that the combination with ATRA would provide a promising novel therapy for Th17 cell-related immune diseases including skin inflammation.

Topics: Animals; CD4-Positive T-Lymphocytes; Cell Differentiation; Cell Proliferation; Cells, Cultured; Dermatitis, Contact; Drug Synergism; Flow Cytometry; Gene Expression; Humans; Interferon-gamma; Interleukin-17; Interleukin-22; Interleukins; Keratolytic Agents; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Receptors, Interleukin; Receptors, Interleukin-1; Reverse Transcriptase Polymerase Chain Reaction; Th17 Cells; Tretinoin; Vitamin D; Vitamins