Abstract
The vitamin A metabolite retinoic acid (RA) plays a fundamental role in cellular functions by activating nuclear receptors. Retinaldehyde dehydrogenase-II (RALDH2) creates localized RA gradients needed for proper embryonic development, but very little is known regarding its regulated expression in adults. Using a human ex vivo model of allergic inflammation by coincubating IgE receptor-activated mast cells (MCs) with blood basophils, we observed prominent induction of a protein that was identified as RALDH2 by mass spectroscopy. RALDH2 was selectively induced in basophils by MC-derived interleukin-3 (IL-3) involving PI3-kinase and NF-kappaB pathways. Importantly, neither constitutive nor inducible RALDH2 expression was detectable in any other human myeloid or lymphoid leukocyte, including dendritic cells. RA generated by RALDH2 in basophils modulates IL-3-induced gene expression in an autocrine manner, providing positive (CD25) as well as negative (granzyme B) regulation. It also acts in a paracrine fashion on T-helper cells promoting the expression of CD38 and alpha4/beta7 integrins. Furthermore, RA derived from IL-3-activated basophils provides a novel mechanism of Th2 polarization. Thus, RA must be viewed as a tightly controlled basophil-derived mediator with a high potential for regulating diverse functions of immune and resident cells in allergic diseases and other Th2-type immune responses.
Original language | English |
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Pages (from-to) | 3762-3771 |
Number of pages | 10 |
Journal | Blood |
Volume | 112 |
Issue number | 9 |
Early online date | 21 May 2008 |
DOIs | |
Publication status | Published - 1 Nov 2008 |
Keywords
- Basophils
- Coculture Techniques
- Enzyme Induction
- Humans
- Inflammation Mediators
- Interleukin-3
- Mast Cells
- NF-kappa B
- Phosphatidylinositol 3-Kinases
- Recombinant Proteins
- Retinal Dehydrogenase
- Signal Transduction
- Th2 Cells
- Tretinoin