title: The human cathelicidin LL-37 modulates the activities of the P2X7 receptor in a structure-dependent manner.
abstract: Extracellular ATP, released at sites of inflammation or tissue damage, activates the P2X(7) receptor, which in turn triggers a range of responses also including cell proliferation. In this study the ability of the human cathelicidin LL-37 to stimulate fibroblast growth was inhibited by commonly used P2X(7) blockers. We investigated the structural requirements of the growth-promoting activity of LL-37 and found that it did not depend on helix sense (the all-d analog was active) but did require a strong helix-forming propensity in aqueous solution (a scrambled analog and primate LL-37 orthologs devoid of this property were inactive). The involvement of P2X(7) was analyzed using P2X(7)-expressing HEK293 cells. LL-37 induced proliferation of these cells, triggered Ca(2+) influx, promoted ethidium bromide uptake, and synergized with benzoyl ATP to enhance the pore and channel functions of P2X(7). The activity of LL-37 had an absolute requirement for P2X(7) expression as it was blocked by the P2X(7) inhibitor KN-62, was absent in cells lacking P2X(7), and was restored by P2X(7) transfection. Of particular interest, LL-37 led to pore-forming activity in cells expressing a truncated P2X(7) receptor unable to generate the non-selective pore typical of the full-length receptor. Our results indicate that P2X(7) is involved in the proliferative cell response to LL-37 and that the structural/aggregational properties of LL-37 determine its capacity to modulate the activation state of P2X(7).
authors.affiliation: Department of Biomedical Sciences and Technology, University of Udine, 33100 Udine, Italy.
authors.forename: Linda
authors.initials: L
authors.lastname: Tomasinsig
authors.forename: Cinzia
authors.initials: C
authors.lastname: Pizzirani
authors.forename: Barbara
authors.initials: B
authors.lastname: Skerlavaj
authors.forename: Patrizia
authors.initials: P
authors.lastname: Pellegatti
authors.forename: Sara
authors.initials: S
authors.lastname: Gulinelli
authors.forename: Alessandro
authors.initials: A
authors.lastname: Tossi
authors.forename: Francesco
authors.initials: F
authors.lastname: Di Virgilio
authors.forename: Margherita
authors.initials: M
authors.lastname: Zanetti