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, Clemens A Dahinden

Research output: Contribution to journalArticle

44 Citations (Scopus)

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 languageEnglish
Pages (from-to)3762-3771
Number of pages10
JournalBlood
Volume112
Issue number9
Early online date21 May 2008
DOIs
Publication statusPublished - 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

Cite this

Human basophils activated by mast cell-derived IL-3 express retinaldehyde dehydrogenase-II and produce the immunoregulatory mediator retinoic acid. / Spiegl, Nicole; Didichenko, Svetlana; McCaffery, Peter; Langen, Hanno; Dahinden, Clemens A.

In: Blood, Vol. 112, No. 9, 01.11.2008, p. 3762-3771.

Research output: Contribution to journalArticle

Spiegl, Nicole ; Didichenko, Svetlana ; McCaffery, Peter ; Langen, Hanno ; Dahinden, Clemens A. / Human basophils activated by mast cell-derived IL-3 express retinaldehyde dehydrogenase-II and produce the immunoregulatory mediator retinoic acid. In: Blood. 2008 ; Vol. 112, No. 9. pp. 3762-3771.
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AB - 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.

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