Interactions of all‐trans retinoic acid and interleukin‐4 in the development of alternatively activated lung macrophages

Abstract

Previously, we showed that all‐trans retinoic acid (ATRA), the most active vitamin A (VA) metabolite, increased in vitro polarization of pig alveolar macrophages (AM) toward an AAM phenotype after interleukin‐4 (IL‐4) treatment and increased the expression of IL‐4 in the lungs of pigs infected with the parasite, Ascaris suum. Others have shown that VA may reduce the susceptibility to additional parasitic infections in animals and humans. The mechanism(s) underlying these effects of VA remain undetermined. Herein, we demonstrate that AM, treated in vitro with IL‐4 or isolated from the lungs of A. suum infected pigs, had 2–8‐fold increases in mRNA expression of alcohol and aldehyde dehydrogenases involved in ATRA generation. At the epigenetic level, ATRA increased mRNA expression of cytochrome P450, family 26, subfamily A, polypeptide 1 (CYP26A1), an enzyme involved in ATRA catabolism, through a 7‐fold increase in methylated activator histone H3K4me3 binding to the CYP26A1 promoter. In contrast, IL‐4 pre‐treatment reduced ATRA‐induced CYP26A1 mRNA expression 4‐fold through a 4 fold increase, above control, in the binding of methylated repressor histone H3K27me3 to the promoter. In conclusion, VA, via metabolism to ATRA, and IL‐4, by favoring conditions that lead to increased ATRA, may synergistically sustain an AAM response to Th2‐dependent responses.Grant Funding Source: USDA/ARS Project Plan 1235–51000‐055–00D.