Anti-inflammatory effect of retinoic acid on experimental autoimmune uveoretinitis.
OBJECTIVE
To determine whether an active metabolite of vitamin A, all-trans retinoic acid (ATRA), reduces inflammation in experimental autoimmune uveoretinitis (EAU).


METHODS
Naive CD4(+) T cells were activated with anti-CD3, anti-CD28 and transforming growth factor (TGF)-beta, in the presence or absence of ATRA. Intracellular expression of transcription factor forkhead box P3 (Foxp3) and interleukin (IL)-17 in the activated CD4(+) T cells was assessed by flow cytometry. C57BL/6 mice were immunised with human interphotoreceptor retinoid binding protein peptide 1-20 (IRBP(1-20)). ATRA was administered intraperitoneally every other day (0.2 mg/mouse per day) from day 0 to day 21. In vivo-primed draining lymph node cells from vehicle-treated or ATRA-treated mice were stimulated with IRBP(1-20) and the culture supernatant fraction was harvested for assay of interferon (IFN)-gamma and IL-17 by ELISA.


RESULTS
ATRA synergised with TGF-beta to induce Foxp3(+) T regulatory cells (Treg) and reciprocally inhibited development of IL-17-producing T helper cells (Th17) induced by TGF-beta and IL-6. ATRA treatment reduced the severity of EAU clinically, and IFN-gamma and IL-17 production were significantly reduced in ATRA-treated mice.


CONCLUSIONS
These findings demonstrate that ATRA treatment ameliorates severity of EAU and reduces the Th1/Th17 responses. ATRA may represent a new therapeutic modality for human refractory uveitis.
Keino
Hiroshi
H
Department of Ophthalmology, Kyorin University School of Medicine, Tokyo, Japan. keino@eye-center.org
Watanabe
Takayo
T
Sato
Yasuhiko
Y
Okada
Annabelle A
AA
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000276:immunology / Q000627:therapeutic use*; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D012173:Retinitis / Q000188:drug therapy* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D014212:Tretinoin / Q000276:immunology / Q000627:therapeutic use*; D014605:Uveitis / Q000188:drug therapy* / Q000276:immunology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; D019947:Receptors, Interleukin-6; D014212:Tretinoin; D007371:Interferon-gamma