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Role of purinergic receptors in the activation of human airway smooth muscle cells by the antimicrobial peptide LL-37

Dept of Pulmonology, C3-P, Leiden University Medical Center, Leiden, The Netherlands

CORRESPONDENCE: Suzanne Zuyderduyn, Dept of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands

Inflammatory cells that infiltrate and surround the airway smooth muscle (ASM) layer express antimicrobial peptides including the cathelicidin LL-37. LL-37 has been shown to activate epithelial cells by transactivation of the epidermal growth factor receptor (EGFR). Previously, we have shown that LL-37-induced IL-8 release by ASM cells was not dependent on either formyl peptide receptors or the EGFR (ATS 2005). In monocytes LL-37 induces processing of IL-1ß through activation of the purinergic P2X₇ receptor. Therefore, the aim of our study was to evaluate the role of purinergic receptors in LL-37-induced activation of ASM cells, and to explore the involvement of several intracellular signalling pathways.

ASM cells were cultured and serum-deprived 24 hours before stimulation with LL-37 (10 µg·ml^–1). The purinergic receptor antagonist suramin and inhibitors of ERK1/2, p38, Src and PI3K were preincubated for one hour. ERK1/2 phosphorylation was assessed by Western Blot, and IL-8 release was determined in supernatants using a sandwich ELISA. RT-PCR was performed for P2X₇ on untreated ASM cells. LL-37 induced ERK1/2 phosphorylation and IL-8 release; both were inhibited by suramin (IL-8: 86%). Inhibitors of ERK1/2, p38 and Src signalling also reduced LL-37-induced IL-8 release (by 67%, 63% and 76%, respectively), suggesting a role for these pathways. P2X₇ mRNA was expressed in ASM cells.

These data show that LL-37-induced IL-8 release is mediated via purinergic receptors, ERK1/2 activation, p38 and Src signalling. Our PCR data are in line with the hypothesis that also in ASM P2X₇ is the purinergic receptor involved in LL-37 signalling, although this needs further investigation.