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The Retinoic Acid Receptor-alpha mediates human T-cell activation and Th2 cytokine and chemokine production.

Dawson HD, Collins G, Pyle R, Key M, Taub DD - BMC Immunol. (2008)

Bottom Line: Here, we have demonstrated that the observed effects using ATRA and 9-cis RA are shared with the clinically useful RAR ligand, 13-cis retinoic acid (13-cis RA), and the retinoic acid receptor-alpha (RAR-alpha)-selective agonist, AM580 but not with the RAR-beta/gamma ligand, 4-hydroxyphenylretinamide (4-HPR).The RAR-alpha-selective agonist, AM580 recapitulated all of the T cell activation and type 2 cytokine-inducing effects of ATRA and 9-cis-RA, while the RAR-alpha-selective antagonist, RO 41-5253, inhibited these effects.These results strongly support a role for RAR-alpha engagement in the regulation of genes and proteins involved with human T cell activation and type 2 cytokine production.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Immunology, Gerontology Research Center, National Institute on Aging, NIH, Baltimore, MD 21224, USA. harry.dawson@ars.usda.gov

ABSTRACT

Background: We have recently demonstrated that all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid (9-cis RA) promote IL-4, IL-5 and IL-13 synthesis, while decreasing IFN-gamma and TNF-alpha expression by activated human T cells and reduces the synthesis of IL-12p70 from accessory cells. Here, we have demonstrated that the observed effects using ATRA and 9-cis RA are shared with the clinically useful RAR ligand, 13-cis retinoic acid (13-cis RA), and the retinoic acid receptor-alpha (RAR-alpha)-selective agonist, AM580 but not with the RAR-beta/gamma ligand, 4-hydroxyphenylretinamide (4-HPR).

Results: The increase in type 2 cytokine production by these retinoids correlated with the expression of the T cell activation markers, CD69 and CD38. The RAR-alpha-selective agonist, AM580 recapitulated all of the T cell activation and type 2 cytokine-inducing effects of ATRA and 9-cis-RA, while the RAR-alpha-selective antagonist, RO 41-5253, inhibited these effects.

Conclusion: These results strongly support a role for RAR-alpha engagement in the regulation of genes and proteins involved with human T cell activation and type 2 cytokine production.

Show MeSH
The effects of various clinically-utilized retinoid compounds on Th1-associated cytokine production by anti-CD3e-activated PBMCs. Supernatants of anti-CD3e-activated PBMCs treated with EtOH or 10-9 to 10-6 M ATRA (○), 9-cis-RA (□), 13-cis-RA (●), or 4-HPR (■) for 48 h were examined for IFN-γ or IL-12 protein levels by ELISA analysis. The values shown represent the average fold change obtained from 4 donors.
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Figure 2: The effects of various clinically-utilized retinoid compounds on Th1-associated cytokine production by anti-CD3e-activated PBMCs. Supernatants of anti-CD3e-activated PBMCs treated with EtOH or 10-9 to 10-6 M ATRA (○), 9-cis-RA (□), 13-cis-RA (●), or 4-HPR (■) for 48 h were examined for IFN-γ or IL-12 protein levels by ELISA analysis. The values shown represent the average fold change obtained from 4 donors.

Mentions: Initial studies focused on comparison between the retinoid compounds, ATRA and 9-cis-RA, and the clinically utilized retinoids, 13-cis-RA and 4-HPR. The results shown in Table 1 and Figure 1 demonstrate the ability of the retinoids, ATRA, 9-cis-RA and 13-cis-RA, to significantly stimulate production of IL-4 from anti-CD3 mAb-stimulated PBMC in a dose-dependent fashion. While ATRA and 9-cis-RA were equipotent in this regard, 13-cis-RA was about 10 fold less active. 4-HPR was slightly inhibitory at low doses and stimulatory only at the highest dose (1 μM). Similarly, the effects of retinoids on IL-5 (Table 1 and Figure 1), and IL-13 (data not shown) production were remarkably similar to that of IL-4. They had no effect on IL-10 (data not shown). For Th1-associated cytokines, 9-cis-RA was approximately 10 times more effective than ATRA at inhibiting IFN-γ production (Table 2 and Figure 2). 13-cis-RA and ATRA were equipotent and 4-HPR was approximately 1,000 fold less effective. For IL-12p70, ATRA was more effective than 9-cis and 13-cis RA at 1 nM but was equipotent at 10–1000 nM.


The Retinoic Acid Receptor-alpha mediates human T-cell activation and Th2 cytokine and chemokine production.

Dawson HD, Collins G, Pyle R, Key M, Taub DD - BMC Immunol. (2008)

The effects of various clinically-utilized retinoid compounds on Th1-associated cytokine production by anti-CD3e-activated PBMCs. Supernatants of anti-CD3e-activated PBMCs treated with EtOH or 10-9 to 10-6 M ATRA (○), 9-cis-RA (□), 13-cis-RA (●), or 4-HPR (■) for 48 h were examined for IFN-γ or IL-12 protein levels by ELISA analysis. The values shown represent the average fold change obtained from 4 donors.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2394516&req=5

Figure 2: The effects of various clinically-utilized retinoid compounds on Th1-associated cytokine production by anti-CD3e-activated PBMCs. Supernatants of anti-CD3e-activated PBMCs treated with EtOH or 10-9 to 10-6 M ATRA (○), 9-cis-RA (□), 13-cis-RA (●), or 4-HPR (■) for 48 h were examined for IFN-γ or IL-12 protein levels by ELISA analysis. The values shown represent the average fold change obtained from 4 donors.
Mentions: Initial studies focused on comparison between the retinoid compounds, ATRA and 9-cis-RA, and the clinically utilized retinoids, 13-cis-RA and 4-HPR. The results shown in Table 1 and Figure 1 demonstrate the ability of the retinoids, ATRA, 9-cis-RA and 13-cis-RA, to significantly stimulate production of IL-4 from anti-CD3 mAb-stimulated PBMC in a dose-dependent fashion. While ATRA and 9-cis-RA were equipotent in this regard, 13-cis-RA was about 10 fold less active. 4-HPR was slightly inhibitory at low doses and stimulatory only at the highest dose (1 μM). Similarly, the effects of retinoids on IL-5 (Table 1 and Figure 1), and IL-13 (data not shown) production were remarkably similar to that of IL-4. They had no effect on IL-10 (data not shown). For Th1-associated cytokines, 9-cis-RA was approximately 10 times more effective than ATRA at inhibiting IFN-γ production (Table 2 and Figure 2). 13-cis-RA and ATRA were equipotent and 4-HPR was approximately 1,000 fold less effective. For IL-12p70, ATRA was more effective than 9-cis and 13-cis RA at 1 nM but was equipotent at 10–1000 nM.

Bottom Line: Here, we have demonstrated that the observed effects using ATRA and 9-cis RA are shared with the clinically useful RAR ligand, 13-cis retinoic acid (13-cis RA), and the retinoic acid receptor-alpha (RAR-alpha)-selective agonist, AM580 but not with the RAR-beta/gamma ligand, 4-hydroxyphenylretinamide (4-HPR).The RAR-alpha-selective agonist, AM580 recapitulated all of the T cell activation and type 2 cytokine-inducing effects of ATRA and 9-cis-RA, while the RAR-alpha-selective antagonist, RO 41-5253, inhibited these effects.These results strongly support a role for RAR-alpha engagement in the regulation of genes and proteins involved with human T cell activation and type 2 cytokine production.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Immunology, Gerontology Research Center, National Institute on Aging, NIH, Baltimore, MD 21224, USA. harry.dawson@ars.usda.gov

ABSTRACT

Background: We have recently demonstrated that all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid (9-cis RA) promote IL-4, IL-5 and IL-13 synthesis, while decreasing IFN-gamma and TNF-alpha expression by activated human T cells and reduces the synthesis of IL-12p70 from accessory cells. Here, we have demonstrated that the observed effects using ATRA and 9-cis RA are shared with the clinically useful RAR ligand, 13-cis retinoic acid (13-cis RA), and the retinoic acid receptor-alpha (RAR-alpha)-selective agonist, AM580 but not with the RAR-beta/gamma ligand, 4-hydroxyphenylretinamide (4-HPR).

Results: The increase in type 2 cytokine production by these retinoids correlated with the expression of the T cell activation markers, CD69 and CD38. The RAR-alpha-selective agonist, AM580 recapitulated all of the T cell activation and type 2 cytokine-inducing effects of ATRA and 9-cis-RA, while the RAR-alpha-selective antagonist, RO 41-5253, inhibited these effects.

Conclusion: These results strongly support a role for RAR-alpha engagement in the regulation of genes and proteins involved with human T cell activation and type 2 cytokine production.

Show MeSH