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Modulation by LL-37 of the Responses of Salivary Glands to Purinergic Agonists

Laboratoires de Biochimie et de Biologie Cellulaire (S.P., S.T., S.Q., M.D.L., J.-P.D.) and Microbiologie, Institute of Pharmacy, Université libre de Bruxelles, Brussels, Belgium (M.T.-H., M.D.); Unité de Recherche sur la Structure et la Fonction des Membranes Biologiques, Faculty of Sciences, Université libre de Bruxelles, Brussels, Belgium (M.V.); and Departamento de Bioquimica y Biologia Molecular, Facultad de Ciencias, Universidad del Pais Vasco, Bilbao, Spain (M.G.-M., A.M.)

The interaction of mice submandibular gland cells with LL-37 (LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES), a cationic peptide with immunomodulatory properties, was investigated. LL-37 at a concentration that did not affect the integrity of the cells increased the uptake of calcium and activated a calcium-insensitive phospholipase A₂ (PLA₂). The small release of ATP induced by LL-37 could not account for this stimulation because apyrase did not significantly block the response to LL-37. The divalent cation magnesium inhibited the response to LL-37, but this inhibition was probably nonspecific because it also inhibited the in vitro bacteriostatic effect of the peptide. The increase of calcium uptake by LL-37 was not affected by 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine (KN-62), a rather specific inhibitor of P2X₇ receptors in mice. LL-37 also increased [Ca²⁺]_i in cells from mice invalidated for these receptors. LL-37 had no effect on the response to carbachol. It inhibited the increase of [Ca²⁺]_i and the activation of phospholipase D by ATP. It potentiated the activation of the PLA₂ by the nucleotide. Finally, LL-37 increased the fluidity of the plasma membrane of submandibular gland cells. In conclusion, our results suggest that LL-37 is an autocrine regulator of submandibular gland cells. It does not stimulate mouse P2X₇ receptors but modulates their responses.

Address correspondence to: Dr. J. P. Dehaye, Laboratoire de Biochimie et de Biologie Cellulaire, Université libre de Bruxelles-Institut de Pharmacie C.P. 205/3, Boulevard du Triomphe, B1050 Bruxelles, Belgium. E-mail: jdehaye{at}ulb.ac.be