Cutting edge: Interleukin 4-dependent mast cell proliferation requires autocrine/intracrine cysteinyl leukotriene-induced signaling.
Reactive mastocytosis (RM) in epithelial surfaces is a consistent Th2-associated feature of allergic disease. RM fails to develop in mice lacking leukotriene (LT) C4 synthase (LTC4S), which is required for cysteinyl leukotriene (cys-LT) production. We now report that IL-4, which induces LTC4S expression by mast cells (MCs), requires cys-LTs, the cys-LT type 1 receptor (CysLT1), and Gi proteins to promote MC proliferation. LTD4 (10-1000 nM) enhanced proliferation of human MCs in a CysLT1-dependent, pertussis toxin-sensitive manner. LTD4-induced phosphorylation of ERK required transactivation of c-kit. IL-4-driven comitogenesis was likewise sensitive to pertussis toxin or a CysLT1-selective antagonist and was attenuated by treatment with leukotriene synthesis inhibitors. Mouse MCs lacking LTC4S or CysLT1 showed substantially diminished IL-4-induced comitogenesis. Thus, IL-4 induces proliferation in part by inducing LTC4S and cys-LT generation, which causes CysLT1 to transactivate c-kit in RM.
Jiang
Yongfeng
Y
Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Kanaoka
Yoshihide
Y
Feng
Chunl
C
Nocka
Karl
K
Rao
Sudhir
S
Boyce
Joshua A
JA
D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003545:Cysteine / Q000378:metabolism*; D005982:Glutathione Transferase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology*; D015289:Leukotrienes / Q000378:metabolism*; D008407:Mast Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D019899:Paracrine Communication / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects
D015289:Leukotrienes; C112381:cysteinyl-leukotriene; D015847:Interleukin-4; D005982:Glutathione Transferase; C041116:leukotriene-C4 synthase; D003545:Cysteine