Human beta-defensin-2 and -3 enhance pro-inflammatory cytokine expression induced by TLR ligands via ATP-release in a P2X7R dependent manner

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• 作者：Daniela Wanke^a ; Katrin Mauch-Mü ; cke^a ; Ernst Holler^b ; Thomas Hehlgans^a ; ^{Thomas.hehlgans@klinik.uni-regensburg.de" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Beta-defensins ; p2x7 receptor ; Pro-inflammatory cytokines ; TLR agonists
• 刊名：Immunobiology
• 出版年：2016
• 出版时间：November 2016
• 年：2016
• 卷：221
• 期：11
• 页码：1259-1265
• 全文大小：795 K

文摘

Our previous results indicate that HBD2 and HBD3 are chemotactic for a broad spectrum of leukocytes in a CCR6- and CCR2-dependent manner. In this study we report that pre-stimulation of primary human macrophages or THP-1 cells with HBD2 or HBD3 results in a synergistic, enhanced expression of pro-inflammatory cytokines and chemokines induced by TLR ligand re-stimulation. Experiments using specific inhibitors of the ATP-gated channel receptor P2X7 or its functional ligand ATP, suggest that the enhanced expression of pro-inflammatory cytokines and chemokines seems to be mediated by P2X7R. Furthermore, our data provide evidence that beta-defensins do not directly interact with P2X7R but rather induce the release of intracellular ATP. Interference with ATP release abrogated the synergistic effect mediated by HBD2 and HBD3 pre-stimulation in THP-1 cells. However, extracellular ATP alone seems not to be sufficient to elicit the enhanced synergistic effect on cytokine and chemokine expression observed by pre-stimulation of primary human macrophages or THP-1 cells with HBD2 or HBD3. Collectively, our findings provide new insights into the molecular mechanisms how HBD2 and HBD3 interact with cells of myeloid origin and demonstrate their immuno-modulating functions during innate immune responses.