Induction of histamine release from human skin mast cells by bradykinin analogs

Abstract

Kinins are potent proinflammatory peptides that induce histamine release from rodent mast cells. We examined the ability of bradykinin, lysylbradykinin and a series of kinin analogs to cause histamine release from human basophils, human lung mast cells and human skin mast cells. At concentrations ranging from 0.1 μM to 1 mM, bradykinin failed to cause histamine release from any of the human histamine-containing cells studied. Lysylbradykinin was also without effect on basophils and lung mast cells, but was a weak secretagogue for human skin mast cells, inducing 5.5 ± 3% (mean ± SD) of total cellular histamine release at a concentration of 10 −5 M. Similarly, when sixteen recently developed bradykinin antagonists were examined, these compounds had no effect on basophils or lung mast cells but all sixteen induced dose-dependent histamine release from skin mast cells. The release process was temperature dependent and, at a concentration of 10 −5 M, the antagonists induced 8–27% histamine release. Although preincubation of cells with 10 −3 M bradykinin or des(Arg 9) bradykinin significantly inhibited antagonist-induced histamine release, the requirement for such high concentrations of these peptides to cause inhibition suggested that histamine release is not mediated by either B 1 or B 2 kinin receptors. To understand further the mechanism of histamine release, we examined a series of bradykinin analogs with single amino acid substitutions in the bradykinin sequence. Replacement of proline 7 in the bradykinin sequence with d-phenylalanine is the essential change used to convert kinin analogs into antagonists, and 10 −5 M [ dPhe 7-bradykinin induced 8–10% histamine release. Other analogs, devoid of antagonist activity, however, such as [ dPhe 6]-bradykinin and [LPhe 7]-bradykinin were able to induce equivalent levels of histamine release. The ability to induce histamine release appears to be related, at least in part, to aromaticity, since [ bTrp 6]-bradykinin and [ dTrp 7]-bradykinin induced greater amounts of histamine release than equivalent [ dPhe]-analogs, causing approximately 20% histamine release at 10 −5 M. By contrast, [ dAla 7]-bradykinin was an ineffective stimulus. In summary, a single amino acid substitution can convert bradykinin into a secretagogue for human skin mast cells. The ability of kinin analogs to induce histamine release from skin mast cells, but not lung mast cells or basophils, emphasizes the heterogeneity of human histamine-containing cells.