Diazepam-binding inhibitor-derived peptides induce intracellular calcium changes and modulate human neutrophil function.
We studied the effects of two diazepam-binding inhibitor (DBI)-derived peptides, triakontatetraneuropeptide (DBI 17-50, TTN) and eiksoneuropeptide (DBI 51-70, ENP), on cytosolic free Ca2+ concentrations ([Ca2+]i), chemotaxis, superoxide anion (O2-) generation, and phagocytosis in human neutrophils. Both TTN and ENP induced a rapid and transient rise of [Ca2+]i. The effect of TTN depended on the presence of extracellular Ca2+, whereas the effect of ENP also persisted after extracellular Ca2+ chelation. TTN induced neutrophil chemotaxis, stimulated O2- generation, and enhanced phagocytosis. ENP did not affect cell migration and oxidative metabolism but enhanced phagocytosis. Both peptides modulated N-formyl-methionyl-leucyl-phenylalanine- and phorbol myristate acetate-induced O2- generation. Because neutrophils express benzodiazepine receptors of the peripheral type (pBRs) and DBI-derived peptides may interact with such receptors, we investigated the possible role of pBRs in TTN- or ENP-induced effects. The synthetic pBR ligand RO 5-4864 increased [Ca2+]i through extracellular Ca2+ influx and this effect was prevented by the pBR antagonist PK-11195. RO 5-4864, however, was ineffective on neutrophil migration and O2- generation and only slightly affected phagocytosis. Moreover, PK-11195 delayed the [Ca2+]i rise induced by TTN but did not significantly affect its extent, and had no effect on the [Ca2+]i rise induced by ENP. We conclude that DBI-derived peptides induce [Ca2+]i changes and modulate neutrophil function mainly through pBR-independent pathways. In view of the wide cell and tissue distribution of DBI in the brain and in peripheral organs, modulation of neutrophil function by DBI-derived peptides may be relevant for both the neuroimmune network and the development and regulation of the inflammatory processes.
Cosentino
M
M
Department of Internal Medicine and Therapeutics, University of Insubria, Varese, Italy.
Marino
F
F
Cattaneo
S
S
Di Grazia
L
L
Francioli
C
C
Fietta
A M
AM
Lecchini
S
S
Frigo
G
G
D000970:Antineoplastic Agents / Q000494:pharmacology; D001570:Benzodiazepinones / Q000494:pharmacology; D002118:Calcium / Q000097:blood*; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D007700:Kinetics; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009479:Neuropeptides / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology*; D010587:Phagocytosis / Q000187:drug effects*; D013481:Superoxides / Q000097:blood*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000970:Antineoplastic Agents; D001570:Benzodiazepinones; D000960:Hypolipidemic Agents; D007546:Isoquinolines; D009479:Neuropeptides; D010446:Peptide Fragments; C117601:diazepam-binding inhibitor (51-70); D013481:Superoxides; C060941:triakontatetraneuropeptide; C028513:4'-chlorodiazepam; D009240:N-Formylmethionine Leucyl-Phenylalanine; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium; C037850:PK 11195