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Published on: May 26, 2023
Vitamin A differentially regulates cytokine expression in respiratory epithelial and macrophage cell lines
Rhiannon R Penkert1, Bart G Jones1, Hans Häcker1
1Department of Infectious Diseases, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
Insights
Vitamin A metabolite retinoic acid affects respiratory cells differently. It downregulates IL-6 in epithelial cells but upregulates it in macrophages, impacting immune responses and explaining past study contradictions.
Area of Science:
- Immunology
- Nutritional Science
- Cell Biology
Background:
- Vitamin A is crucial for children's respiratory health and immune function.
- Vitamin A's effects on immune responses, like IL-6 regulation, appear contradictory in different contexts.
- Retinoic acid (RA), a vitamin A metabolite, is investigated for its role in immune modulation.
Purpose of the Study:
- To investigate the cell-specific effects of retinoic acid (RA) on respiratory tract epithelial cells (LETs) and macrophages (MACs).
- To resolve apparent contradictions in how vitamin A influences immune responses, particularly IL-6 production.
- To understand the impact of RA on immune cell signaling pathways relevant to respiratory infections.
Main Methods:
- Utilized cell line models of respiratory tract epithelial cells (LETs) and macrophages (MACs).
- Exposed cell lines to lipopolysaccharide (LPS) or Sendai virus to mimic respiratory pathogen exposure.
- Analyzed the effects of retinoic acid (RA) on gene and protein expression, including IL-6, MCP-1, GMCSF, IL-10, and RARβ transcripts.
Main Results:
- Retinoic acid (RA) downregulated IL-6 in epithelial cells (LETs) but upregulated it in macrophages (MACs) upon stimulation.
- RA increased transcript levels of MCP-1, GMCSF, and IL-10 specifically in macrophages.
- RA upregulated RARβ transcripts in epithelial cells, suggesting cell-specific metabolic regulation.
Conclusions:
- The effects of retinoic acid on immune responses are highly dependent on the target cell type.
- Cell-specific effects of RA help explain discrepancies in previous vitamin A research.
- Clinical trials involving vitamin A supplementation should consider these cell-specific immune modulations.
Abstract:
Vitamin A is an essential nutrient for the protection of children from respiratory tract disease. Supplementation with vitamin A is frequently prescribed in the clinical setting, in part to combat deficiencies among children in developing countries, and in part to treat respiratory infections in clinical trials. This vitamin influences immune responses via multiple, and sometimes seemingly contradictory mechanisms. For example, in separate reports, vitamin A was shown to decrease Th17 T-cell activity by downregulating IL-6, and to promote B cell production of IgA by upregulating IL-6. To explain these apparent contradictions, we evaluated the effects of retinoic acid (RA), a key metabolite of vitamin A, on cell lines of respiratory tract epithelial cells (LETs) and macrophages (MACs). When triggered with LPS or Sendai virus, a mouse respiratory pathogen, these two cell lines experienced opposing influences of RA on IL-6. Both IL-6 protein production and transcript levels were downregulated by RA in LETs, but upregulated in MACs. RA also increased transcript levels of MCP-1, GMCSF, and IL-10 in MACs, but not in LETs. Conversely, when LETs, but not MACs, were exposed to RA, there was an increase in transcripts for RARβ, an RA receptor with known inhibitory effects on cell metabolism. Results help explain past discrepancies in the literature by demonstrating that the effects of RA are cell target dependent, and suggest close attention be paid to cell-specific effects in clinical trials involving vitamin A supplements.
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