Abstract
BackgroundHuman hemokinin-1 (hHK-1) and endokinins are peptides of the tachykinin family encoded by the TAC4 gene. TAC4 and hHK-1 expression as well as effects of hHK-1 in the lung and airways remain however unknown and were explored in this study.MethodsRT-PCR analysis was performed on human bronchi to assess expression of tachykinin and tachykinin receptors genes. Enzyme immunoassay was used to quantify hHK-1, and effects of hHK-1 and endokinins on contraction of human and guinea pig airways were then evaluated, as well as the role of hHK-1 on cytokines production by human lung parenchyma or bronchi explants and by lung macrophages.ResultsIn human bronchi, expression of the genes that encode for hHK-1, tachykinin NK1-and NK2-receptors was demonstrated. hHK-1 protein was found in supernatants from explants of human bronchi, lung parenchyma and lung macrophages. Exogenous hHK-1 caused a contractile response in human bronchi mainly through the activation of NK2-receptors, which blockade unmasked a NK1-receptor involvement, subject to a rapid desensitization. In the guinea pig trachea, hHK-1 caused a concentration-dependant contraction mainly mediated through the activation of NK1-receptors. Endokinin A/B exerted similar effects to hHK-1 on both human bronchi and guinea pig trachea, whereas endokinins C and D were inactive. hHK-1 had no impact on the production of cytokines by explants of human bronchi or lung parenchyma, or by human lung macrophages.ConclusionsWe demonstrate endogenous expression of TAC4 in human bronchi, the encoded peptide hHK-1 being expressed and involved in contraction of human and guinea pig airways.
Highlights
Human hemokinin-1 and endokinins are peptides of the tachykinin family encoded by the TAC4 gene
Tachykinins, tachykinin receptors and neutral endopeptidase expression In human bronchi, TAC4, TACR1 and TACR2 mRNAs were found in all samples whereas TAC1 and TACR3 mRNAs were not detected
In addition to TAC4 mRNA expression, Human hemokinin-1 (hHK-1) protein was found in the supernatants of bronchial explants (1.40 ± 0.31 pg/100 mg (n = 11)), parenchyma explants (1.15 ± 0.29 pg/100 mg (n = 11)) and lung macrophages (1.85 ± 0.89 pg/106 cells (n = 6)) cultured for 24 hours in the presence of phosphoramidon
Summary
Human hemokinin-1 (hHK-1) and endokinins are peptides of the tachykinin family encoded by the TAC4 gene. TAC4 and hHK-1 expression as well as effects of hHK-1 in the lung and airways remain unknown and were explored in this study. The mammalian tachykinins are a family of structurally related peptides which are derived from three distinct genes. TAC4 was identified recently in lymphoid B haematopoietic cells of the mouse bone marrow and encodes for hemokinin-1 (HK-1) [3]. The same peptide is encoded by the rat TAC4 [4] and is named rat/mouse hemokinin-1 (r/mHK-1). TAC4 encodes for hemokinin-1 (hHK-1), but its sequence is different from its murine counterpart. A more detailed analysis of the TAC4 gene in humans showed that
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