Human basophils activated by mast cell-derived IL-3 express retinaldehyde dehydrogenase-II and produce the immunoregulatory mediator retinoic acid.
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.
Spiegl
Nicole
N
Institute of Immunology, University Hospital Bern, Inselspital, Bern, Switzerland.
Didichenko
Svetlana
S
McCaffery
Peter
P
Langen
Hanno
H
Dahinden
Clemens A
CA
D001491:Basophils / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D018920:Coculture Techniques; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D007377:Interleukin-3 / Q000378:metabolism / Q000494:pharmacology*; D008407:Mast Cells / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D050697:Retinal Dehydrogenase / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects; D018418:Th2 Cells / Q000276:immunology; D014212:Tretinoin / Q000276:immunology / Q000378:metabolism*
D018836:Inflammation Mediators; D007377:Interleukin-3; D016328:NF-kappa B; D011994:Recombinant Proteins; D014212:Tretinoin; D050697:Retinal Dehydrogenase; D019869:Phosphatidylinositol 3-Kinases