1α,25-Dihydroxyvitamin D3 and all-trans retinoic acid synergistically inhibit the differentiation and expansion of Th17 cells.
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.
Ikeda
Utako
U
Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Japan.
Wakita
Daiko
D
Ohkuri
Takayuki
T
Chamoto
Kenji
K
Kitamura
Hidemitsu
H
Iwakura
Yoichiro
Y
Nishimura
Takashi
T
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003877:Dermatitis, Contact / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D004357:Drug Synergism; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D007378:Interleukins / Q000235:genetics; D007641:Keratolytic Agents / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018123:Receptors, Interleukin / Q000235:genetics; D017472:Receptors, Interleukin-1 / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058504:Th17 Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology; D014815:Vitamins / Q000494:pharmacology; D000097043:Interleukin-22
D007371:Interferon-gamma; D020381:Interleukin-17; D007378:Interleukins; D007641:Keratolytic Agents; D018123:Receptors, Interleukin; D017472:Receptors, Interleukin-1; D014212:Tretinoin; D014807:Vitamin D; D014815:Vitamins; D000097043:Interleukin-22; C515500:IL23R protein, human; C118756:dihydroxy-vitamin D3