title: Autocrine hemokinin-1 functions as an endogenous adjuvant for IgE-mediated mast cell inflammatory responses.
abstract: BACKGROUND
  Efficient development of atopic diseases requires interactions between allergen and adjuvant to initiate and amplify the underlying inflammatory responses. Substance P (SP) and hemokinin-1 (HK-1) are neuropeptides that signal through the neurokinin-1 receptor (NK1R) to promote inflammation. Mast cells initiate the symptoms and tissue effects of atopic disorders, secreting TNF and IL-6 after FcεRI cross-linking by antigen-IgE complexes (FcεRI-activated mast cells [FcεRI-MCs]). Additionally, MCs express the NK1R, suggesting an adjuvant role for NK1R agonists in FcεRI-MC-mediated pathologies; however, in-depth research addressing this relevant aspect of MC biology is lacking.
  
  
  OBJECTIVE
  We sought to investigate the effect of NK1R signaling and the individual roles of SP and HK-1 as potential adjuvants for FcεRI-MC-mediated allergic disorders.
  
  
  METHODS
  Bone marrow-derived mast cells (BMMCs) from C57BL/6 wild-type (WT) or NK1R(-/-) mice were used to investigate the effects of NK1R signaling on FcεRI-MCs. BMMCs generated from Tac1(-/-) mice or after culture with Tac4 small interfering RNA were used to address the adjuvancy of SP and HK-1. WT, NK1R(-/-), and c-Kit(W-sh/W-sh) mice reconstituted with WT or NK1R(-/-) BMMCs were used to evaluate NK1R signaling on FcεRI-MC-mediated passive local and systemic anaphylaxis and on airway inflammation.
  
  
  RESULTS
  FcεRI-activated MCs upregulated NK1R and HK-1 transcripts and protein synthesis, without modifying SP expression. In a positive signaling loop HK-1 promoted TNF and IL-6 secretion by MC degranulation and protein synthesis, the latter through the phosphoinositide 3-kinase/Akt/nuclear factor κB pathways. In vivo NK1R signaling was necessary for the development of passive local and systemic anaphylaxis and airway inflammation.
  
  
  CONCLUSIONS
  FcεRI stimulation of MCs promotes autocrine secretion of HK-1, which signals through NK1R to provide adjuvancy for efficient development of FcεRI-MC-mediated disorders.
authors.affiliation: Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, Pa.
authors.forename: Tina L
authors.initials: TL
authors.lastname: Sumpter
authors.affiliation: Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, Pa.
authors.forename: Chin H
authors.initials: CH
authors.lastname: Ho
authors.affiliation: Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, Pa.
authors.forename: Anna R
authors.initials: AR
authors.lastname: Pleet
authors.affiliation: Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, Pa.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Tkacheva
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pa; Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pa.
authors.forename: William J
authors.initials: WJ
authors.lastname: Shufesky
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pa; Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pa.
authors.forename: Darling M
authors.initials: DM
authors.lastname: Rojas-Canales
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pa; Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pa; Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pa.
authors.forename: Adrian E
authors.initials: AE
authors.lastname: Morelli
authors.affiliation: Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, Pa; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pa; McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pa. Electronic address: adrianal@pitt.edu.
authors.forename: Adriana T
authors.initials: AT
authors.lastname: Larregina
mesh_terms: D000707:Anaphylaxis / Q000276:immunology / Q000378:metabolism; D000818:Animals; D019898:Autocrine Communication; D004195:Disease Models, Animal; D005260:Female; D007073:Immunoglobulin E / Q000276:immunology*; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism*; D015850:Interleukin-6 / Q000096:biosynthesis; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D017455:Receptors, IgE / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D015398:Signal Transduction; D015320:Tachykinins / Q000378:metabolism*; D048069:Tumor Necrosis Factors / Q000096:biosynthesis
chemical_list: D015850:Interleukin-6; D017455:Receptors, IgE; D018040:Receptors, Neurokinin-1; D015320:Tachykinins; D048069:Tumor Necrosis Factors; C507968:hemokinin-1; D007073:Immunoglobulin E
keywords: FcεRI; Hemokinin-1; IL-6; IgE; TNF; airway inflammation; mast cells; neurokinin-1 receptor; passive anaphylaxis; substance P