title: Signaling pathways activated by a protease allergen in basophils.
abstract: Allergic diseases represent a significant burden in industrialized countries, but why and how the immune system responds to allergens remain largely unknown. Because many clinically significant allergens have proteolytic activity, and many helminths express proteases that are necessary for their life cycles, host mechanisms likely have evolved to detect the proteolytic activity of helminth proteases, which may be incidentally activated by protease allergens. A cysteine protease, papain, is a prototypic protease allergen that can directly activate basophils and mast cells, leading to the production of cytokines, including IL-4, characteristic of the type 2 immune response. The mechanism of papain's immunogenic activity remains unknown. Here we have characterized the cellular response activated by papain in basophils. We find that papain-induced IL-4 production requires calcium flux and activation of PI3K and nuclear factor of activated T cells. Interestingly, papain-induced IL-4 production was dependent on the immunoreceptor tyrosine-based activation motif (ITAM) adaptor protein Fc receptor γ-chain, even though the canonical ITAM signaling was not activated by papain. Collectively, these data characterize the downstream signaling pathway activated by a protease allergen in basophils.
authors.affiliation: Howard Hughes Medical Institute and Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Rachel K
authors.initials: RK
authors.lastname: Rosenstein
authors.affiliation: Howard Hughes Medical Institute and Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Jelena S
authors.initials: JS
authors.lastname: Bezbradica
authors.affiliation: Howard Hughes Medical Institute and Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Shuang
authors.initials: S
authors.lastname: Yu
authors.affiliation: Howard Hughes Medical Institute and Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520 ruslan.medzhitov@yale.edu.
authors.forename: Ruslan
authors.initials: R
authors.lastname: Medzhitov
mesh_terms: D034001:Adaptor Protein Complex Subunits / Q000502:physiology; D000485:Allergens / Q000494:pharmacology*; D000818:Animals; D001491:Basophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D007114:Immunization; D018793:Interleukin-13 / Q000096:biosynthesis / Q000235:genetics; D000067596:Interleukin-33; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000235:genetics; D007378:Interleukins / Q000494:pharmacology; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000378:metabolism; D010206:Papain / Q000276:immunology / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D017455:Receptors, IgE / Q000235:genetics / Q000502:physiology; D017452:Receptors, IgG / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D013047:Specific Pathogen-Free Organisms
chemical_list: D034001:Adaptor Protein Complex Subunits; D000485:Allergens; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D015853:Cysteine Proteinase Inhibitors; C485701:Fcgr1 protein, mouse; C506535:Il33 protein, mouse; D018793:Interleukin-13; D000067596:Interleukin-33; D007378:Interleukins; D050778:NFATC Transcription Factors; D017455:Receptors, IgE; D017452:Receptors, IgG; D015847:Interleukin-4; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D010206:Papain; D007930:Leucine; C024974:E 64
keywords: allergen; basophil; signaling