TY - JOUR
T1 - Interleukin-23 promotes Th17 differentiation by inhibiting T-bet and FoxP3 and is required for elevation of Interleukin-22, but not Interleukin-21, in autoimmune experimental arthritis
AU - Mus, Adriana M.C.
AU - Cornelissen, Ferry
AU - Asmawidjaja, Patrick S.
AU - Van Hamburg, Jan Piet
AU - Boon, Louis
AU - Hendriks, Rudi W.
AU - Lubberts, Erik
PY - 2010/4
Y1 - 2010/4
N2 - Objective. To examine the role of interleukin-23 (IL-23) in subgroup polarization of IL-17A-positive and/or interferon-γ (IFNγ)-positive T cells in autoimmune disease-prone DBA/1 mice with and without collagen-induced arthritis. Methods. A magnetic-activated cell sorting system was used to isolate CD4+ T cells from the spleen of naive and type II collagen (CII)-immunized DBA/1 mice. These CD4+ T cells were stimulated in vitro under Th0, Th1, or different Th17 culture conditions. Intracellular staining for IL-17A and IFNγ was evaluated by flow cytometry. In addition, Th17 cytokines and T helper-specific transcription factors were analyzed by enzyme-linked immunosorbent assay and/or quantitative polymerase chain reaction. Results. In CD4+ T cells from naive DBA/1 mice, IL-23 alone hardly induced retinoic acid-related orphan receptor γt (RORγt), Th17 polarization, and Th17 cytokines, but it inhibited T-bet expression. In contrast, transforming growth factor β1 (TGFβ1)/IL-6 was a potent inducer of RORγt, RORα, IL-17A, IL-17F, IL-21, and FoxP3 in these cells. In contrast to TGFβ1/IL-6, IL-23 was critical for the induction of IL-22 in CD4+ T cells from both naive and CII-immunized DBA/1 mice. Consistent with these findings, IL-23 showed a more pronounced induction of the IL-17A+IFNγ- subset in CD4+ T cells from CII-immunized mice. However, in CD4+ T cells from naive mice, IL-23 significantly increased the TGFβ1/IL-6-induced Th17 polarization, including elevated levels of IL-17A and IL-17F and decreased expression of T-bet and FoxP3. Of note, the IL-23-induced increase in IL-17A and IL-17F levels was prevented in T-bet-deficient mice. Conclusion. IL-23 promotes Th17 differentiation by inhibiting T-bet and FoxP3 and is required for elevation of IL-22, but not IL-21, levels in autoimmune arthritis. These data indicate different mechanisms for IL-23 and TGFβ1/IL-6 at the transcription factor level during Th17 differentiation in autoimmune experimental arthritis.
AB - Objective. To examine the role of interleukin-23 (IL-23) in subgroup polarization of IL-17A-positive and/or interferon-γ (IFNγ)-positive T cells in autoimmune disease-prone DBA/1 mice with and without collagen-induced arthritis. Methods. A magnetic-activated cell sorting system was used to isolate CD4+ T cells from the spleen of naive and type II collagen (CII)-immunized DBA/1 mice. These CD4+ T cells were stimulated in vitro under Th0, Th1, or different Th17 culture conditions. Intracellular staining for IL-17A and IFNγ was evaluated by flow cytometry. In addition, Th17 cytokines and T helper-specific transcription factors were analyzed by enzyme-linked immunosorbent assay and/or quantitative polymerase chain reaction. Results. In CD4+ T cells from naive DBA/1 mice, IL-23 alone hardly induced retinoic acid-related orphan receptor γt (RORγt), Th17 polarization, and Th17 cytokines, but it inhibited T-bet expression. In contrast, transforming growth factor β1 (TGFβ1)/IL-6 was a potent inducer of RORγt, RORα, IL-17A, IL-17F, IL-21, and FoxP3 in these cells. In contrast to TGFβ1/IL-6, IL-23 was critical for the induction of IL-22 in CD4+ T cells from both naive and CII-immunized DBA/1 mice. Consistent with these findings, IL-23 showed a more pronounced induction of the IL-17A+IFNγ- subset in CD4+ T cells from CII-immunized mice. However, in CD4+ T cells from naive mice, IL-23 significantly increased the TGFβ1/IL-6-induced Th17 polarization, including elevated levels of IL-17A and IL-17F and decreased expression of T-bet and FoxP3. Of note, the IL-23-induced increase in IL-17A and IL-17F levels was prevented in T-bet-deficient mice. Conclusion. IL-23 promotes Th17 differentiation by inhibiting T-bet and FoxP3 and is required for elevation of IL-22, but not IL-21, levels in autoimmune arthritis. These data indicate different mechanisms for IL-23 and TGFβ1/IL-6 at the transcription factor level during Th17 differentiation in autoimmune experimental arthritis.
UR - http://www.scopus.com/inward/record.url?scp=77950548359&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/art.27336
DO - https://doi.org/10.1002/art.27336
M3 - Article
C2 - 20131264
SN - 0004-3591
VL - 62
SP - 1043
EP - 1050
JO - Arthritis and rheumatism
JF - Arthritis and rheumatism
IS - 4
ER -