In vitro human polymorphonuclear leukocyte chemokinesis and human monocyte chemotaxis are different activities of aminoterminal and carboxyterminal substance P

Summary Polymorphonuclear leukocytes (PMNL) are a component of the inflammatory response to neurogenic mediators. Using the micropore filter approach, the authors studied the chemoattracting properties of tachykinins, including substance P (SP), neurokinin A (NKA) and neurokinin B (NKB), and that of calcitonin gene-related peptide (CGRP) for human PMNL in vitro and now show that SP in near nanomolar concentrations stimulates locomotion of human PMNL. Locomotion of PMNL is induced by SP, aminoterminal SP (1–9) and the SP receptor antagonist [d-pro², d-trp^7,9]-SP (DPDT) but not by carboxyterminal SP (3–11), NKA, NKB, or CGRP suggesting that the aminoterminal amino acids arginine and proline, are essential residues of SP in activation of PMNL locomotion. In contrast, the migratory effect of SP on monocytes resides in the carboxyterminal SP amino acid sequence, which is in agreement with carboxyterminal, SP receptor-mediated chemotaxis of human monocytes previously shown by others. From the known structure-activity relationships for SP receptors it is concluded that induction of PMNL migration by SP does not involve neurokinin-1 (NK-1), NK-2 or NK-3 receptors. Checkerboard analysis reveals that PMNL locomotion by SP is not dependent on concentration gradients and thus represents chemokinesis, which is enhancement of speed and/or frequency of locomotion. One cannot exclude that this action of SP on PMNL is mediated by the aminoterminal sequence via yet unknown SP receptors. Since structure-activity relationships appear to be similar to the mast cell degranulating actions of tachykinins, which also critically depend on the aminoterminal sequence, it may correspondingly be regarded as non-receptorial mechanism, due to membrane interaction of the basic groups in the N-terminal region of the peptide.Presented in part at the International Symposium on Interactions between the Neuroendocrine and Immune Systems in Copanello, Italy, June 1–5, 1988Send offprint requests toC. J. Wiedermann at the above address