T Helper Cell Type 2 Cytokines Coordinately Regulate Immunoglobulin E–Dependent Cysteinyl Leukotriene Production by Human Cord Blood–Derived Mast Cells
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- Fred H. Hsieh
- aDepartment of Medicine, Harvard Medical School, Boston, Massachusetts 02115
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- Bing K. Lam
- aDepartment of Medicine, Harvard Medical School, Boston, Massachusetts 02115
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- John F. Penrose
- aDepartment of Medicine, Harvard Medical School, Boston, Massachusetts 02115
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- K. Frank Austen
- aDepartment of Medicine, Harvard Medical School, Boston, Massachusetts 02115
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- Joshua A. Boyce
- aDepartment of Medicine, Harvard Medical School, Boston, Massachusetts 02115
抄録
<jats:p>Human mast cells (hMCs) derived in vitro from cord blood mononuclear cells exhibit stem cell factor (SCF)-dependent comitogenic responses to T helper cell type 2 (Th2) cytokines. As cysteinyl leukotriene (cys-LT) biosynthesis is a characteristic of immunoglobulin (Ig)E-activated mucosal hMCs, we speculated that Th2 cytokines might regulate eicosanoid generation by hMCs. After passive sensitization for 5 d with IgE in the presence of SCF, anti-IgE–stimulated hMCs elaborated minimal cys-LT (0.1 ± 0.1 ng/106 hMCs) and abundant prostaglandin (PG)D2 (16.2 ± 10.3 ng/106 hMCs). Priming of hMCs by interleukin (IL)-4 with SCF during passive sensitization enhanced their anti-IgE–dependent histamine exocytosis and increased their generation of both cys-LT (by 27-fold) and PGD2 (by 2.5-fold). Although priming with IL-3 or IL-5 alone for 5 d with SCF minimally enhanced anti-IgE–mediated cys-LT generation, these cytokines induced further six- and fourfold increases, respectively, in IgE-dependent cys-LT generation when provided with IL-4 and SCF; this occurred without changes in PGD2 generation or histamine exocytosis relative to hMCs primed with IL-4 alone. None of these cytokines, either alone or in combination, substantially altered the levels of cytosolic phospholipase A2 (cPLA2), 5-lipoxygenase (5-LO), or 5-LO activating protein (FLAP) protein expression by hMCs. In contrast, IL-4 priming dramatically induced the steady-state expression of leukotriene C4 synthase (LTC4S) mRNA within 6 h, and increased the expression of LTC4S protein and functional activity in a dose- and time-dependent manner, with plateaus at 10 ng/ml and 5 d, respectively. Priming by either IL-3 or IL-5, with or without IL-4, supported the localization of 5-LO to the nucleus of hMCs. Thus, different Th2-derived cytokines target distinct steps in the 5-LO/LTC4S biosynthetic pathway (induction of LTC4S expression and nuclear import of 5-LO, respectively), each of which is necessary for a full integrated functional response to IgE-dependent activation, thus modulating the effector phenotype of mature hMCs.</jats:p>
収録刊行物
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- The Journal of Experimental Medicine
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The Journal of Experimental Medicine 193 (1), 123-134, 2001-01-01
Rockefeller University Press
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詳細情報 詳細情報について
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- CRID
- 1362825895466589056
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- NII論文ID
- 30017415663
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- ISSN
- 15409538
- 00221007
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