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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.

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Related in: MedlinePlus

The effects of ATRA on Th1 and Th2 cytokine production are primarily mediated through RAR-α with minimal involvement of liganded RXRs. IL-12p70 and IFN-γ (Panel A) and IL-4 and IL-5 (Panel B) proteins were quantitated by ELISA in supernatants of 48 h, anti-CD3,-activated PBMC treated in the absence or presence of EtOH, ATRA (10-8 M), or the RAR-α agonist, AM580 (10-8 M) and in the presence or absence of EtOH (□) or the RXR agonist (10-8 M, ■). The above data are representative of the results from two different donors examined.
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Figure 8: The effects of ATRA on Th1 and Th2 cytokine production are primarily mediated through RAR-α with minimal involvement of liganded RXRs. IL-12p70 and IFN-γ (Panel A) and IL-4 and IL-5 (Panel B) proteins were quantitated by ELISA in supernatants of 48 h, anti-CD3,-activated PBMC treated in the absence or presence of EtOH, ATRA (10-8 M), or the RAR-α agonist, AM580 (10-8 M) and in the presence or absence of EtOH (□) or the RXR agonist (10-8 M, ■). The above data are representative of the results from two different donors examined.

Mentions: Because ATRA and 9-cis RA were relatively equipotent in their effects on IL-4, IL-5 and IL-13 synthesis, we hypothesized that liganded RXRs may be only minimally involved in the type 2 cytokine-inducing effects of ATRA. Previous studies that examined the ability of certain retinoids to inhibit IL-12p70 synthesis and to induce thymocyte apoptosis, found 9-cis-RA to be at least 10 times more potent than ATRA on a molar basis (5, 23). The authors of these studies have suggested that given the enhanced effects of 9-cis-RA that RXRs were involved in this process [14,36]. To directly address this question, we have examined the ability of an RXR-selective retinoid, SR11345, in conjunction with ATRA or the RAR-α-selective retinoid, AM580 to modulate type 1 and 2 cytokine production in two independent human donors. Previous reports have demonstrated a molecular cooperative or obligate interactions of liganded RARs receptors with liganded RXRs by using combinations of RAR- and RXR-selective ligands [14,37,38]. The results in Figure 8 demonstrate the ability of the RXR agonist, SR11345, to inhibit IL-12p70 and IFN-γ synthesis (Panel A), but with little to no additional activity on type 2- cytokine synthesis alone or in combination with RARα agonists (Panel B). Similar results were obtained for IL-4 and IL-5 levels using purified human T cells (data not shown). These results and those in Table 2, suggest that liganded RXRs appear to exert inhibitory effects on type 1 cytokine production alone but are less efficacious than RARα agonists and do not appear to be playing a role in type 2 cytokine responses.


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 ATRA on Th1 and Th2 cytokine production are primarily mediated through RAR-α with minimal involvement of liganded RXRs. IL-12p70 and IFN-γ (Panel A) and IL-4 and IL-5 (Panel B) proteins were quantitated by ELISA in supernatants of 48 h, anti-CD3,-activated PBMC treated in the absence or presence of EtOH, ATRA (10-8 M), or the RAR-α agonist, AM580 (10-8 M) and in the presence or absence of EtOH (□) or the RXR agonist (10-8 M, ■). The above data are representative of the results from two different donors examined.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 8: The effects of ATRA on Th1 and Th2 cytokine production are primarily mediated through RAR-α with minimal involvement of liganded RXRs. IL-12p70 and IFN-γ (Panel A) and IL-4 and IL-5 (Panel B) proteins were quantitated by ELISA in supernatants of 48 h, anti-CD3,-activated PBMC treated in the absence or presence of EtOH, ATRA (10-8 M), or the RAR-α agonist, AM580 (10-8 M) and in the presence or absence of EtOH (□) or the RXR agonist (10-8 M, ■). The above data are representative of the results from two different donors examined.
Mentions: Because ATRA and 9-cis RA were relatively equipotent in their effects on IL-4, IL-5 and IL-13 synthesis, we hypothesized that liganded RXRs may be only minimally involved in the type 2 cytokine-inducing effects of ATRA. Previous studies that examined the ability of certain retinoids to inhibit IL-12p70 synthesis and to induce thymocyte apoptosis, found 9-cis-RA to be at least 10 times more potent than ATRA on a molar basis (5, 23). The authors of these studies have suggested that given the enhanced effects of 9-cis-RA that RXRs were involved in this process [14,36]. To directly address this question, we have examined the ability of an RXR-selective retinoid, SR11345, in conjunction with ATRA or the RAR-α-selective retinoid, AM580 to modulate type 1 and 2 cytokine production in two independent human donors. Previous reports have demonstrated a molecular cooperative or obligate interactions of liganded RARs receptors with liganded RXRs by using combinations of RAR- and RXR-selective ligands [14,37,38]. The results in Figure 8 demonstrate the ability of the RXR agonist, SR11345, to inhibit IL-12p70 and IFN-γ synthesis (Panel A), but with little to no additional activity on type 2- cytokine synthesis alone or in combination with RARα agonists (Panel B). Similar results were obtained for IL-4 and IL-5 levels using purified human T cells (data not shown). These results and those in Table 2, suggest that liganded RXRs appear to exert inhibitory effects on type 1 cytokine production alone but are less efficacious than RARα agonists and do not appear to be playing a role in type 2 cytokine responses.

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
Related in: MedlinePlus