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Blood, 1 November 2008, Vol. 112, No. 9, pp. 3762-3771.
Prepublished online as a Blood First Edition Paper on May 21, 2008; DOI 10.1182/blood-2008-01-135251.
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Submitted January 24, 2008
Accepted April 23, 2008
Human basophils activated by mast cell-derived IL-3 express retinaldehyde dehydrogenase-II and produce the immunoregulatory mediator retinoic acid
Nicole Spiegl, Svetlana Didichenko, Peter McCaffery, Hanno Langen, and Clemens A. Dahinden*
Institute of Immunology, University Hospital Bern, Bern, Switzerland
Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom
Proteomics Initiative, Roche Center for Medical Genomics, Basel, Switzerland
* Corresponding author; email: clemens.dahinden{at}iib.unibe.ch.
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 co-incubating IgE-receptor-activated mast cells (MCs) with blood basophils, we observed prominent induction of a protein which was identified as RALDH2 by mass spectroscopy. RALDH2 was selectively induced in basophils by MC-derived IL-3 involving PI-3-kinase and NF- B 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  4/ 7-integrins. Furthermore, RA derived from IL-3-activated basophils skews naive T cells towards Th2, providing 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.
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