Non-IgE-dependent activation of human lung- and cord blood-derived mast cells is induced by eosinophil major basic protein and modulated by the membrane form of stem cell factor.
The allergic reaction begins with the antigen-induced aggregation of occupied high-affinity IgE receptors expressed on mast cell surface, their activation, and the release of proinflammatory mediators that cause the "early phase" of this process. In addition, mast cell activation induces the onset of a "late phase" reaction characterized by the tissue infiltration of inflammatory cells, mainly eosinophils. We have hypothesized that during the late phase mast cells interact with and are activated by eosinophils. Here we report that highly purified human lung mast cells became responsive to eosinophil major basic protein (MBP) when in coculture with human lung fibroblasts. In addition, cord blood-derived mast cells maintained in coculture with 3T3 fibroblasts released more histamine and prostaglandin D(2) (PGD(2)) compared with cells maintained in suspension. The fibroblast-derived membrane form of stem cell factor (SCF) was found to be involved in the mast cell increased responsiveness to MBP. In fact, cord blood-derived mast cells cocultured with 3T3 in the presence of antisense for SCF or cocultured with fibroblasts that do not express the membrane form of SCF were inhibited in their histamine-releasing activity toward MBP. In addition, this form of SCF induced the expression of a pertussis toxin-sensitive G(i) protein, G(i3) that interacts with MBP to trigger mast cell non-IgE-dependent activation in a manner similar to other cationic compounds such as compound 48/80. Mast cell responsiveness to eosinophil mediators is a potentially novel evidence for an alternative pathway of allergen-independent activation able to contribute to the perpetuation of allergy.
Piliponsky
Adrian M
AM
Department of Pharmacology, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Gleich
Gerald J
GJ
Nagler
Arnon
A
Bar
Ilan
I
Levi-Schaffer
Francesca
F
D016475:3T3 Cells / Q000187:drug effects; D000328:Adult; D000818:Animals; D001798:Blood Proteins / Q000494:pharmacology / Q000502:physiology*; D018929:Cell Culture Techniques / Q000379:methods; D018920:Coculture Techniques; D047091:Eosinophil Granule Proteins; D005312:Fetal Blood / Q000166:cytology*; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D005786:Gene Expression Regulation / Q000187:drug effects; D020962:Heterotrimeric GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D006636:Histamine Release / Q000187:drug effects*; D006801:Humans; D006967:Hypersensitivity / Q000503:physiopathology; D007073:Immunoglobulin E / Q000502:physiology; D007231:Infant, Newborn; D008168:Lung / Q000166:cytology*; D008407:Mast Cells / Q000378:metabolism / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D009928:Organ Specificity; D010529:Peritoneal Cavity / Q000166:cytology; D037342:Pertussis Toxin / Q000494:pharmacology; D015230:Prostaglandin D2 / Q000378:metabolism*; D020033:Protein Isoforms / Q000502:physiology; D051381:Rats; D012260:Ribonucleases; D019089:Stem Cell Factor / Q000502:physiology*
D001798:Blood Proteins; D047091:Eosinophil Granule Proteins; D008565:Membrane Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D020033:Protein Isoforms; D019089:Stem Cell Factor; D007073:Immunoglobulin E; D037342:Pertussis Toxin; D012260:Ribonucleases; C498819:GNAI3 protein, human; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C417708:Gnai3 protein, mouse; C498820:Gnai3 protein, rat; D020962:Heterotrimeric GTP-Binding Proteins; D015230:Prostaglandin D2