Abstract
We explored the relation between vasoactive intestinal peptide (VIP), CRTH2, and eosinophil recruitment. It is shown that CRTH2 expression by eosinophils from allergic rhinitis (AR) patients and eosinophil cell line (Eol-1 cells) was up-regulated by VIP treatment. This was functional and resulted in exaggerated migratory response of cells against PGD2. Nasal challenge of AR patients resulted in a significant increase of VIP contents in nasal secretion (ELISA), and the immunohistochemical studies of allergic nasal tissues showed significant expression of VIP in association with intense eosinophil recruitment. Biochemical assays showed that VIP-induced eosinophil chemotaxis from AR patients and Eol-1 cells was mediated through the CRTH2 receptor. Cell migration against VIP was sensitive to protein kinase C (PKC) and protein kinase A (PKA) inhibition but not to tyrosine kinase or p38 MAPK inhibition or calcium chelation. Western blot demonstrated a novel CRTH2-mediated cytosol-to-membrane translocation of PKC-ε, PKC-δ, and PKA-α, -γ, and -IIαreg in Eol-1 cells upon stimulation with VIP. Confocal images and FACS demonstrated a strong association and co-localization between VIP peptide and CRTH2 molecules. Further, VIP induced PGD2 secretion from eosinophils. Our results demonstrate the first evidence of association between VIP and CRTH2 in recruiting eosinophils.
Highlights
Ligand receptor ligation regulates immune-inflammatory cell chemotaxis
The current interest in airway eosinophilic inflammation is to discover the molecular events resulting in eosinophil recruitment and to develop an effective mode of therapy
We showed that the allergic nasal tissue secretes vasoactive intestinal peptide (VIP) in doses that attracted human eosinophils in Boyden chambers
Summary
Ligand receptor ligation regulates immune-inflammatory cell chemotaxis. Results: Vasoactive intestinal peptide and prostaglandin D2 share the CRTH2 receptor in inducing eosinophil chemotaxis. It is shown that CRTH2 expression by eosinophils from allergic rhinitis (AR) patients and eosinophil cell line (Eol-1 cells) was up-regulated by VIP treatment This was functional and resulted in exaggerated migratory response of cells against PGD2. Biochemical assays showed that VIP-induced eosinophil chemotaxis from AR patients and Eol-1 cells was mediated through the CRTH2 receptor. The novel chemoattractant receptor-homologous molecule expressed by TH2 cells, basophils, and eosinophils (CRTH2) gained a lot of attention as a promoter for PGD2-induced eosinophilia in allergic airway diseases [12,13,14,15,16]. In an allergic rhinitis murine model, it has been demonstrated that the PGD2-CRTH2 interaction is elevated following pollen sensitization This resulted in specific IgE and IgG1 production, nasal eosinophilia, and IL-4 and IL-5 production by submandibular lymph node cells. Immunohistochemical analysis of nasal tissue from allergic chronic rhinosinusitis (ACRS) patients and nasal provocation challenges allowed us to validate our biochemical results and to have an applied in vivo correlation
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