title: Tyrosine kinase inhibition is an important factor for gene expression of CRTH2 in human eosinophils and lymphocytes: A novel mechanism for explaining eosinophils recruitment by the neuro-immune axis in allergic rhinitis.
abstract: We recently shown a novel neuro-immune competition between vasoactive intestinal peptide (VIP) and PGD2 for CRTH2 receptor, and that genistein augmented VIP and PGD2-induced eosinophil chemotaxis. However, there are neither studies on the CRTH2 gene expression in allergic rhinitis (AR) nor in the effect of tyrosine kinase inhibitors in CRTH2 gene regulation. Our Objectives were to study the gene expression modulation of CRTH2 receptor in AR patients and the effect of tyrosine kinase inhibitors (TKIs) on CRTH2 gene modulation. Nasal provocation tests, ELISA, qRT-PCR, western blot, flow cytometry and chemotaxis assays in modified micro-Boyden chambers, were all used, to achieve our objectives. Herein we show that AR patients increased the amounts of VIP and PGD2 in their nasal secretions in the early phase reaction, however CRTH2 gene expression from leukocytes recovered in their nasal secretions was upregulated only during the late phase reaction. The TKIs; Genistein, Erbstatin and Herbimycin A, induced the gene expression of CRTH2 and increased the protein content of CRTH2 in both human lymphocytes and eosinophils. This was functional as PGD2/VIP-induced eosinophil chemotaxis was augmented by the TKIs and inhibited by pervanadate, the tyrosine phosphatase inhibitor. These results open channels for therapeutic modalities targeting CRTH2 molecules in AR.
authors.affiliation: Department of Otolaryngology and Head and Neck Surgery, Liege University Hospital-CHU, Liege, Belgium; Department of Pathology, Laboratory of Experimental Pathology, University of Liege, Liege, Belgium. Electronic address: amrel_shazly@hotmail.com.
authors.forename: A E
authors.initials: AE
authors.lastname: El-Shazly
authors.affiliation: Department of Pathology, Laboratory of Experimental Pathology, University of Liege, Liege, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Roncarati
authors.affiliation: Department of Pathology, Laboratory of Experimental Pathology, University of Liege, Liege, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Lejeune
authors.affiliation: Department of Otolaryngology and Head and Neck Surgery, Liege University Hospital-CHU, Liege, Belgium.
authors.forename: P P
authors.initials: PP
authors.lastname: Lefebvre
authors.affiliation: Department of Pathology, Laboratory of Experimental Pathology, University of Liege, Liege, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Delvenne
mesh_terms: D000328:Adult; D039741:Antigens, Dermatophagoides / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D004804:Eosinophils / Q000187:drug effects* / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D019833:Genistein / Q000627:therapeutic use; D006801:Humans; D006873:Hydroquinones / Q000627:therapeutic use; D008214:Lymphocytes / Q000187:drug effects* / Q000276:immunology; D008297:Male; D009297:Nasal Mucosa / Q000473:pathology*; D015213:Neuroimmunomodulation; D015230:Prostaglandin D2 / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000235:genetics / Q000378:metabolism*; D065631:Rhinitis, Allergic / Q000188:drug therapy* / Q000276:immunology; D017828:Rifabutin / Q000031:analogs & derivatives / Q000627:therapeutic use; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism
chemical_list: D039741:Antigens, Dermatophagoides; D006873:Hydroquinones; D047428:Protein Kinase Inhibitors; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D017828:Rifabutin; D014660:Vasoactive Intestinal Peptide; C020754:herbimycin; D019833:Genistein; D015230:Prostaglandin D2; C048212:erbstatin; C036293:prostaglandin D2 receptor
keywords: Allergic rhinitis; CRTH2; Late phase reaction; Leukocytes; Tyrosine kinase inhibitors